US9487512B2 - (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors - Google Patents

(Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors Download PDF

Info

Publication number
US9487512B2
US9487512B2 US14/352,711 US201214352711A US9487512B2 US 9487512 B2 US9487512 B2 US 9487512B2 US 201214352711 A US201214352711 A US 201214352711A US 9487512 B2 US9487512 B2 US 9487512B2
Authority
US
United States
Prior art keywords
compound
formula
phenylcyclopropyl
ring
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US14/352,711
Other languages
English (en)
Other versions
US20150025054A1 (en
Inventor
Alberto Ortega Muñoz
Matthew Colin Thor Fyfe
Marc Martinell Pedemonte
Maria de los Angeles Estiarte Martinez
Nuria Valls Vidal
Guido Kurz
Julio Cesar Castro Palomino Laria
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oryzon Genomics SA
Original Assignee
Oryzon Genomics SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oryzon Genomics SA filed Critical Oryzon Genomics SA
Priority to US14/352,711 priority Critical patent/US9487512B2/en
Publication of US20150025054A1 publication Critical patent/US20150025054A1/en
Assigned to ORYZON GENOMICS S.A. reassignment ORYZON GENOMICS S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CASTRO PALOMINO LARIA, JULIO CESAR, FYFE, MATTHEW COLIN THOR, KURZ, GUIDO, MARTINEZ, MARIA DE LOS ANGELES ESTIARTE, PEDEMONTE, MARC MARTINELL, VIDAL, NURIA VALLS, MUÑOZ, ALBERTO ORTEGA
Application granted granted Critical
Publication of US9487512B2 publication Critical patent/US9487512B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the invention relates to (hetero)aryl cyclopropylamine compounds, particularly compounds of formula I, Ia, Ia-1, Ib and Ic, more particularly compounds of formula I and Ia, as described and defined herein, and their use in therapy, including e.g., in the treatment or prevention of cancer, a neurological disease, or a viral infection.
  • DNA promoter methylation is associated with suppression of gene expression.
  • blockbuster VidazaTM Another class of modifications involve histones which form the protein scaffold that DNA is normally associated with (coiled around) in eukaryotic cells. Histones play a crucial role in organizing DNA and the regulated coiling and uncoiling of DNA around the histones is critical in controlling gene expression—coiled DNA is typically not accessible for gene transcription.
  • histone acetylation histone lysine methylation
  • histone arginine methylation histone ubiquinylation
  • histone sumoyiation many of which modify accessibility to the associated DNA by the cells transcriptional machinery.
  • histone marks serve to recruit various protein complexes involved in transcription and repression.
  • An increasing number of studies are painting an intricate picture of how various combinations of histone marks control gene expression in cell-type specific manner and a new term has been coined to capture this concept: the histone code.
  • Histone acetyl transferase and histone deacetylases are the catalytic machines involved in modulation of this histone mark although typically these enzymes are parts of multiprotein complexes containing other proteins involved in reading and modifying histone marks.
  • the components of these protein complexes are typically cell-type specific and typically comprise transcriptional regulators, repressors, co-repressors, receptors associated with gene expression modulation (e.g., estrogen or androgen receptor).
  • Histone deacetylase inhibitors alter the histone acetylation profile of chromatin.
  • histone deacetylase inhibitors like Vorinostat (SAHA), Trichostatin A (TSA), and many others have been shown to alter gene expression in various in vitro and in vivo animal models.
  • SAHA Vorinostat
  • TSA Trichostatin A
  • histone deacetylase inhibitors have demonstrated activity in the cancer setting and are being investigated for oncology indications as well as for neurological conditions and other diseases.
  • histone methylation including lysine and arginine methylation.
  • the methylation status of histone lysines has recently been shown to be important in dynamically regulating gene expression.
  • LSD1 Lysine Specific Demethylase-1
  • MAO-A, MAO-B and LSD1 flavin dependent amine oxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/or nitrogen carbon bonds.
  • LSD1 has been recognized as an interesting target for the development of new drugs to treat cancer, neurological diseases and other conditions.
  • Cyclopropylamine containing compounds are known to inhibit a number of medically important targets including amine oxidases like Monoamine Oxidase A (MAO-A; or MAOA), Monoamine Oxidase B (MAO-B; or MAOB), and Lysine Specific Demethylase-1 (LSD1).
  • Tranylcypromine also known as 2-phenylcyclopropylamine
  • Parnate® and one of the best known examples of a cyclopropylamine
  • MAO-A inhibition may cause undesired side effects, it would be desirable to identify cyclopropylamine derivatives that exhibit potent LSD1 inhibitory activity while being devoid of or having substantially reduced MAO-A inhibitory activity.
  • the present invention relates to the identification of compounds and their use in treating or preventing diseases.
  • the invention provides (hetero)aryl cyclopropylamine compounds, including the compounds of Formula I, Ia, Ia-1, Ib and Ic, and particularly the compounds I, Ia and Ia-1, as described and defined herein.
  • the present invention particularly provides a compound of Formula I, Ia, Ia-1, Ib and Ic, and particularly a compound of Formula I, Ia and Ia-1, pharmaceutical compositions comprising a compound of Formula I, Ia, Ia-1, Ib or Ic, and particularly a compound of Formula I, Ia or Ia-1, and a pharmaceutically acceptable carrier, and their uses for treating diseases.
  • One use of the compound of Formula I, Ia, Ia-1, Ib and Ic is for treating or preventing cancer.
  • Another use for the compound of Formula I, Ia, Ia-1, Ib and Ic is to inhibit LSD1.
  • the invention thus relates to a compound of Formula I, Ia, Ia-1, Ib or Ic, and particularly a compound of Formula I, Ia or Ia-1, for use in treating or preventing human disease.
  • the present invention further relates to a compound of Formula I, Ia, Ia-1, Ib and Ic, and particularly a compound of Formula I, Ia or Ia-1, for use in treating or preventing cancer.
  • the present invention further relates to a compound of Formula I, Ia, Ia-1, Ib and Ic, and particularly a compound of Formula I, Ia or Ia-1, for use in treating or preventing a neurological disease.
  • the present invention further relates to a compound of Formula I, Ia, Ia-1, Ib and Ic, and particularly a compound of Formula I, Ia or Ia-1, for use in treating or preventing a viral infection.
  • the present invention provides a compound of Formula I and relates, in particular, to the compound of Formula I for use as a medicament:
  • the present invention provides a compound of Formula I wherein R w , R x , R y and R z are each hydrogen, i.e. a compound of formula Ia, and relates, in particular, to the compound of Formula Ia for use as a medicament:
  • the invention provides a compound of formula Ia as defined above wherein the substituents of the cyclopropyl moiety -A-B and —NH-L 2 -D are in the trans-configuration, i.e. a compound of formula Ia-1:
  • a compound of formula Ia-1 therefore relates to the individual optically active trans isomers as well as any mixtures thereof.
  • the invention provides a compound of formula I as defined above wherein each R w , R x , R y and R z is independently selected from hydrogen, halo and C 1-4 alkyl with the proviso that at least one of R w , R x , R y and R z is not hydrogen; that compound is referred to as a compound of formula Ib in the following.
  • R w is selected from halo and C 1-4 alkyl, preferably from fluoro and methyl, and each R x , R y and R z is hydrogen.
  • a compound of formula I wherein R w is selected from halo and C 1-4 alkyl, preferably from fluoro and methyl, and each R x , R y and R z is hydrogen is referred to as a compound of formula Ic in the following.
  • all isomers including all stereoisomers and mixtures thereof, of the compounds of formula I, Ia, Ia-1, Ib and Ic.
  • All salts and all solvates, preferably pharmaceutically acceptable salts and solvates, of the compounds of formula I, Ia, Ia-1, Ib and Ic are also encompassed within the scope of the invention.
  • all physical forms (including amorphous and crystalline forms) of any such compounds are also encompassed within the scope of the invention.
  • any reference to a compound of formula I, Ia, Ia-1, Ib or Ic should be construed, unless otherwise indicated, as a reference to a compound of formula I, Ia, Ia-1, Ib or Ic (respectively), any isomer thereof (including any stereoisomer thereof or any mixtures thereof), any salt thereof (including any pharmaceutically acceptable salt thereof), any solvate thereof (including any pharmaceutically acceptable solvate thereof), and any physical form thereof.
  • the compounds of formula Ia including also the compounds of formula Ia-1, are particularly preferred compounds according to the present invention.
  • the most preferred compounds of the invention are the compounds of formula Ia-1.
  • any chemical drawing or formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds of the invention.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Particularly preferred are the deuterated forms of the compounds of the invention, i.e.
  • Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In addition to the unlabeled form, all isotopically labeled forms of the compounds of formula I, Ia, Ia-1, Ib and Ic are included within the scope of the invention.
  • the compounds of formula I, Ia, Ia-1, Ib and Ic are potent inhibitors of LSD1 and therefore can be useful for the treatment or prevention of any disease associated with LSD1.
  • the invention thus provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Ia, Ia-1, Ib or Ic and a pharmaceutically acceptable carrier.
  • Preferred embodiments of the compound of Formula I, Ia, Ia-1, Ib and Ic, e.g. for use in the compositions of the invention, are defined and described herein below in more detail.
  • the invention provides a method of treating or preventing a disease comprising administering, to a patient (preferably a human) in need of such treatment or prevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (as described above or as defined in the embodiments thereof described below) effective to treat or prevent said disease.
  • a patient preferably a human
  • an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic as described above or as defined in the embodiments thereof described below
  • such disease is a disease associated with LSD1.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (as described above or as defined in the embodiments thereof as described below) for use as a medicament.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic for use in the treatment or prevention of a disease associated with LSD1.
  • the invention provides a method of inhibiting LSD1 activity comprising administering, to a patient in need of treatment, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic sufficient to inhibit LSD1 activity.
  • the patient is a human.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic as herein defined for use as a LSD1 inhibitor. Preferred embodiments of the compounds of Formula I, Ia, Ia-1, Ib or Ic for use herein are as described in more detail below.
  • the invention provides a method of treating or preventing cancer comprising administering, to a patient (preferably a human) in need of such treatment or prevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or as defined in the embodiments described in more detail herein) sufficient to treat or prevent such cancer.
  • the invention provides a method of treating or preventing a cancer wherein said cancer is chosen from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma and myeloma, comprising administering to a patient (preferably a human) in need of such treatment or prevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or as defined in the embodiments described in more detail herein) sufficient to treat or prevent such cancer.
  • leukemia including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (C
  • said cancer is chosen from prostate, brain, colorectal, lung, breast, skin, and blood cancer.
  • the cancer is prostate cancer.
  • the cancer is lung cancer.
  • the cancer is brain cancer.
  • the cancer is blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia).
  • the cancer is breast cancer.
  • the cancer is colorectal cancer.
  • the cancer is lymphoma. In one specific aspect, the cancer is myeloma.
  • the method comprises administering a therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic sufficient for treating or preventing said cancer.
  • the therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic is an amount sufficient to inhibit LSD1.
  • the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. While the present invention relates to both the treatment and the prevention of cancer, the treatment of cancer is particularly preferred.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or as defined in the embodiments described in more detail herein), for use in the treatment or prevention of cancer.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic for use in the treatment or prevention of a cancer wherein said cancer is chosen from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma and myeloma.
  • leukemia including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (
  • said cancer is chosen from prostate, brain, colorectal, lung, breast, skin, and blood cancer.
  • the cancer is prostate cancer.
  • the cancer is lung cancer.
  • the cancer is brain cancer.
  • the cancer is blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia).
  • the cancer is breast cancer.
  • the cancer is colorectal cancer.
  • the cancer is lymphoma. In one specific aspect, the cancer is myeloma.
  • a therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic sufficient for treating or preventing said cancer is administered.
  • the therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic is an amount sufficient to inhibit LSD1.
  • the therapeutically effective amount is an amount sufficient to modulate histone methylation levels.
  • the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels.
  • the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels.
  • the invention provides a method of treating or preventing a neurological disease (e.g., a neurodegenerative disease) comprising administering, to a patient in need of such treatment or prevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) sufficient to treat or prevent said neurological disease.
  • a neurological disease e.g., a neurodegenerative disease
  • the invention provides a method of treating or preventing a neurological disease wherein said neurological disease is selected from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Dementia with Lewy Bodies, or Frontotemporal Dementia, particularly from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, or Dementia with Lewy Bodies, comprising administering to a patient (preferably a human) in need of such treatment or prevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or as defined in the embodiments described in more detail herein) sufficient to treat or prevent such neurological disease.
  • a patient preferably a human
  • the method comprises administering a therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic sufficient for treating or preventing said neurological disease.
  • the therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic is an amount sufficient to inhibit LSD1.
  • the therapeutically effective amount is an amount sufficient to modulate histone methylation levels.
  • the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels.
  • the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in the treatment or prevention of a neurological disease (e.g., a neurodegenerative disease).
  • a neurological disease e.g., a neurodegenerative disease
  • said neurological disease is selected from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Dementia with Lewy Bodies and Frontotemporal Dementia, particularly from depression, Alzheimer's disease, Huntington disease, Parkinson's disease and Dementia with Lewy Bodies.
  • a therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic sufficient for treating or preventing said neurological disease is administered.
  • the therapeutically effective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic is an amount sufficient to inhibit LSD1.
  • the therapeutically effective amount is an amount sufficient to modulate histone methylation levels.
  • the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels.
  • the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels.
  • the invention provides a method of treating or preventing a viral infection comprising administering to a patient in need thereof (preferably a human) an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) sufficient to treat or prevent said viral infection
  • the invention also provides a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in treating or preventing a viral infection.
  • the viral infection is a herpesvirus infection.
  • the herpesvirus infection is caused by and/or associated with a herpesvirus chosen from HSV-1, HSV-2, and Epstein-Barr virus.
  • the viral infection is caused by and/or associated with HIV.
  • the viral infection is caused by and/or associated with a Hepadnavirus (i.e., a virus of the Hepadnaviridae family), particularly Hepatitis B virus (HBV).
  • the viral infection is caused by and/or associated with a Flavivirus (i.e., a virus of the Flaviviridae family), particularly Hepatitis C virus (HCV), yellow fever virus, West Nile virus, Dengue virus or Japanese encephalitis virus, and more preferably HCV.
  • the invention provides a method for treating or preventing viral reactivation after latency, the method comprising administering to an individual (preferably a human) a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein). Accordingly, the invention also provides a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for use in treating or preventing viral reactivation after latency.
  • the virus that is reactivating is a herpesvirus.
  • the herpesvirus that is reactivating is chosen from HSV-1, HSV-2, and Epstein-Barr virus.
  • the virus that is reactivating is HSV.
  • the virus that is reactivating is HIV.
  • the invention provides the use of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for the manufacture of a medicament for the treatment or prevention of cancer.
  • said cancer is chosen from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma and myeloma.
  • leukemia including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic
  • the invention provides the use of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for the manufacture of a medicament for the treatment or prevention of a neurological disease (e.g., a neurodegenerative disease).
  • a neurological disease e.g., a neurodegenerative disease
  • said neurological disease is selected from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Dementia with Lewy Bodies, or Frontotemporal Dementia, particularly from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, and Dementia with Lewy Bodies.
  • the invention provides the use of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for the manufacture of a medicament for the treatment or prevention of a viral infection.
  • said viral infection is a herpesvirus infection (e.g., a herpesvirus infection caused by and/or associated with a herpesvirus chosen from HSV-1, HSV-2, and Epstein-Barr virus) or a viral infection caused by and/or associated with HIV.
  • said viral infection is caused by and/or associated with a Hepadnavirus, particularly Hepatitis B virus (HBV).
  • said viral infection is caused by and/or associated with a Flavivirus, particularly Hepatitis C virus (HCV), yellow fever virus, West Nile virus, Dengue virus or Japanese encephalitis virus, and more preferably HCV.
  • the invention provides the use of a compound of Formula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described in more detail herein) for the manufacture of a medicament for the treatment or prevention of viral reactivation after latency.
  • the virus that is reactivating is a herpesvirus (e.g., HSV-1, HSV-2, or Epstein-Barr virus), HSV, or HIV.
  • the invention provides a method for identifying a compound which is a selective inhibitor of LSD1, the method comprising selecting or providing a compound of Formula I, Ia, Ia-1, Ib or Ic as defined herein, and determining the ability of the compound to inhibit LSD1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSD1 to a greater extent than MAO-A and/or MAO-B is identified as a LSD1 selective inhibitor.
  • the compound of this aspect that is an LSD1 inhibitor can be used to treat disease, particularly human disease.
  • the invention provides a process for the preparation of a compound of formula I, or a salt thereof, which comprises reacting a compound of formula II
  • A, B, R w , R x , R y , R z have the meaning disclosed above in relation to a compound of formula I, with a compound of formula IIIa, IIIb or IIIc
  • D has the meaning disclosed above in relation to a compound of formula I, and wherein any amino group that may be present in D is optionally protected with a protecting group,
  • the present invention relates to the identification of compounds and their use in treating and preventing diseases.
  • the present invention provides compounds of Formula I, Ia, Ia-1, Ib and Ic, pharmaceutical compositions comprising a compound of Formula I, Ia Ia-1, Ib or Ic and a pharmaceutically acceptable carrier, and their use for treating diseases.
  • One use of the compounds of Formula I, Ia, Ia-1, Ib and Ic is for treating cancer.
  • the present invention provides a compound of Formula I and relates, in particular, to the compound of Formula I for use as a medicament.
  • each R w , R x , R y and R z is independently selected from hydrogen, halo and C 1-4 alkyl. In one embodiment, each R w , R x , R y and R z is independently selected from hydrogen, fluoro and C 1-4 alkyl, preferably from hydrogen, fluoro and methyl. In another embodiment, each R w , R x , R y and R z is independently selected from hydrogen and fluoro.
  • R w is fluoro and each R x , R y and R z is independently selected from hydrogen, halo and C 1-4 alkyl; preferably, R w is fluoro and each R x , R y and R z is hydrogen.
  • R z is fluoro and each R w , R x and R y is independently selected from hydrogen, halo and C 1-4 alkyl; preferably, R z is fluoro and each R w , R x and R y is hydrogen.
  • R w and R z are fluoro and each R x and R y is independently selected from hydrogen, halo and C 1-4 alkyl; preferably, R w and R z are fluoro and each R x and R y is hydrogen.
  • R w is selected from hydrogen, halo and C 1-4 alkyl, preferably from hydrogen, fluoro and methyl, and each R x , R y and R z is hydrogen.
  • each R w , R x , R y and R z is hydrogen.
  • a compound of formula I wherein each R w , R x , R y and R z is hydrogen is a compound of formula Ia, which can be depicted as follows:
  • each R w , R x , R y and R z is independently selected from hydrogen, halo and C 1-4 alkyl with the proviso that at least one of R w , R x , R y and R z is not hydrogen, this is compound of formula Ib.
  • R w is selected from halo and C 1-4 alkyl, preferably fluoro and methyl
  • each R x , R y and R z is hydrogen.
  • a compound of formula I wherein R w is selected from halo and C 1-4 alkyl, preferably fluoro and methyl, and each R x , R y and R z is hydrogen is a compound of formula Ic.
  • R w is methyl.
  • the invention also relates to a compound of formula Ia, Ia-1, Ib and Ic as defined above, and in particular to a compound of formula Ia, Ia-1, Ib and Ic for use as a medicament.
  • the group A is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 1 .
  • A is aryl (preferably phenyl or naphthyl) optionally substituted with one or more R 1 .
  • A is phenyl optionally substituted with one or more R 1 .
  • A is naphthyl (preferably 2-naphthyl) optionally substituted with one or more R 1 .
  • A is heteroaryl optionally substituted with one or more R 1 .
  • A is monocyclic heteroaryl optionally substituted with one or more R 1 .
  • A is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl, said naphthyl or said monocyclic heteroaryl is optionally substituted with one or more R 1 .
  • A is monocyclic aryl (i.e. phenyl) or monocyclic heteroaryl, wherein said monocyclic aryl or said monocyclic heteroaryl is optionally substituted with one or more R 1 .
  • A is phenyl, pyridyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl, wherein A (i.e. said phenyl, said pyridyl, said thiophenyl, said pyrrolyl, said furanyl, or said thiazolyl) is optionally substituted with one or more R 1 . Still more preferably, A is phenyl, pyridyl or thiazolyl, wherein A is optionally substituted with one or more R 1 . Even more preferably, A is phenyl, 3-pyridyl or 5-thiazolyl, as shown below:
  • A is optionally substituted with one or more R 1 .
  • A is phenyl or pyridyl, preferably phenyl or 3-pyridyl. In another embodiment, A is phenyl. In another embodiment, A is pyridyl, preferably 3-pyridyl. In another embodiment, A is thiazolyl, preferably 5-thiazolyl. In one embodiment, A has 0, 1 or 2 substituents R 1 . In a further embodiment, A has 0 or 1 substituent R 1 . In a further embodiment, A has 0 substituent R 1 . In a further embodiment, A has 1 or 2 substituents R 1 . In a further embodiment, A has 1 substituent R 1 .
  • B is hydrogen, R 1 or -L 1 -E. In one embodiment, B is -L 1 -E. In another embodiment, B is hydrogen or R 1 . In a further embodiment, B is hydrogen. In another embodiment, B is R 1 .
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 .
  • E is an aryl group (e.g., phenyl, naphthyl or anthracenyl) optionally substituted with one or more R 2 .
  • E is a heteroaryl group (e.g., pyridinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, indolyl, pyrazolyl, indazolyl, imidazolyl or benzimidazolyl) optionally substituted with one or more R 2 .
  • a heteroaryl group e.g., pyridinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl,
  • E is pyridinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, indolyl, indazolyl, imidazolyl or benzimidazolyl, wherein said pyridinyl, said thiophenyl, said pyrrolyl, said furanyl, said thiazolyl, said oxazolyl, said isoxazolyl, said oxadiazolyl, said thiadiazolyl, said triazinyl, said pyridazinyl, said pyrazinyl, said pyrimidinyi, said quinolyl, said indolyl, said indazolyi, said imidazolyi or
  • E is monocyclic aryl (i.e. phenyl) or monocyclic heteroaryl, wherein said monocyclic aryl or said monocyclic heteroaryl is optionally substituted with one or more R 2 .
  • E is phenyl or pyridinyl, wherein said phenyl or said pyridinyl is optionally substituted with one or more R 2 .
  • E has 0, 1, 2 or 3 substituents R 2 .
  • E has 0, 1 or 2 substituents R 2 .
  • E has 0 or 1 substituents R 2 .
  • E has 0 substituents R 2 .
  • E has 1 substituent R 2 .
  • E is phenyl optionally substituted with one or more R 2 .
  • E is phenyl optionally substituted with one, two or three R 2 .
  • E is phenyl optionally substituted with one or two R 2 .
  • E is phenyl optionally substituted with one R 2 .
  • E is phenyl.
  • E is phenyl substituted with one, two or three, preferably one or two, R 2 .
  • E is heteroaryl, preferably monocyclic heteroaryl, optionally substituted with one or more (preferably one, two or three) R 2 .
  • E is heteroaryl, preferably monocyclic heteroaryl.
  • E is heteroaryl (preferably monocyclic heteroaryl) substituted with one, two or three, preferably one or two, R 2 .
  • L 1 is a bond, —O—, —NH—, —N(C 1-4 alkyl)-, C 1-4 alkylene or heteroC 1-4 alkylene.
  • said heteroC 1-4 alkylene is —(CH 2 ) x —NH—, or —(CH 2 ) x —O—, wherein x is 1, 2, 3 or 4; still more preferably, said —(CH 2 ) x —NH— or —(CH 2 ) x —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —(CH 2 ) x — group.
  • said heteroC 1-4 alkylene is —CH 2 —NH— or —CH 2 —O—, wherein said —CH 2 —NH— and —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond, —O—, —NH—, —N(C 1-4 alkyl)-, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —NH—, or —CH 2 —O—.
  • L 1 is a bond, —O—, —NH—, —N(C 1-4 alkyl)-, —CH 2 —NH—, or —CH 2 —O—.
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—.
  • L 1 is a bond, —O—, —NH—, or —CH 2 —NH—. In another embodiment, L 1 is a bond or —CH 2 —O—. In another embodiment, L 1 is —NH— or —CH 2 —NH—. In a further embodiment, L 1 is a bond.
  • L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, C 1-4 alkylene or heteroC 1-4 alkylene; preferably, L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —NH—, or —CH 2 —O—; more preferably L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, —CH 2 —NH—, or —CH 2 —O—; even more preferably L 1 -O—, —NH—, —CH 2 —NH—, or —CH 2 —O—; and particularly preferably L 1 is —CH 2 —O—.
  • L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, C 1-4 alkylene, —(CH 2 ) x —NH—, —SO 2 NH— or —SO 2 N(CH 3 )—, wherein x is 1, 2, 3 or 4; preferably L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, C 1-4 alkylene, or —CH 2 —NH—, and more preferably L 1 is —O—, —NH— or —CH 2 —NH—.
  • said —(CH 2 ) x —NH—, —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • B is -L 1 -E;
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ; and
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein the groups —CH 2 —NH— and —CH 2 —O— are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • B is -L 1 -E;
  • E is phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, indolyl, indazolyl, imidazolyl or benzimidazolyl, wherein said phenyl, said pyridinyl, said thiophenyl, said pyrrolyl, said furanyl, said thiazolyl, said oxazolyl, said isoxazolyl, said oxadiazolyl, said thiadiazolyl, said triazinyl, said pyridazinyl, said pyrazinyl, said pyrimidinyl, said quinolyl,
  • B is -L 1 -E; E is phenyl optionally substituted with one or more R 2 ; and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein the groups —CH 2 —NH— and —CH 2 —O— are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • B is -L 1 -E; E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ; and L 1 is a bond or —CH 2 —O—, wherein the group —CH 2 —O— is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • B is -L 1 -E; E is phenyl optionally substituted with one or more R 2 ; and L 1 is a bond or —CH 2 —O—, wherein the group —CH 2 —O— is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • B is -L 1 -E; E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ; and L 1 is a bond.
  • B is -L 1 -E; E is aryl, pyridinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, indolyl, indazolyl, imidazolyl or benzimidazolyl, wherein said aryl, said pyridinyl, said thiophenyl, said pyrrolyl, said furanyl, said thiazolyl, said oxazolyl, said isoxazolyl, said
  • B is -L 1 -E; E is aryl, wherein said aryl is optionally substituted with one or more R 2 ; and L 1 is a bond.
  • B is -L 1 -E; E is phenyl optionally substituted with one or more R 2 ; and L 1 is a bond.
  • B is -L 1 -E; E is pyridinyl optionally substituted with one or more R 2 ; and L 1 is a bond.
  • B is -L 1 -E; E is aryl or heteroaryl; and L 1 is a bond.
  • B is -L 1 -E;
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ; and
  • L 1 is —CH 2 —O—, wherein the group —CH 2 —O— is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • B is -L 1 -E; E is heteroaryl (preferably monocyclic heteroaryl, more preferably pyridinyl), wherein said heteroaryl is optionally substituted with one or more R 2 ; and L 1 is —CH 2 —O—, wherein the group —CH 2 —O— is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • B is -L 1 -E; E is phenyl optionally substituted with one or more R 2 ; and L 1 is —CH 2 —O—, wherein the group —CH 2 —O— is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • B is -L 1 -E;
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ;
  • L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, C 1-4 alkylene, —SO 2 NH— or —SO 2 N(CH 3 )—, wherein x is 1, 2, 3 or 4, preferably L 1 is —O—, —NH—, —N(C 1-4 alkyl)-, C 1-4 alkylene, or —CH—NH—, and more preferably L 1 is —O—, —NH— or —CH 2 —NH— wherein the group —CH 2 —NH— is linked to ring A through the N atom and to ring E through the —CH 2 — group.
  • B is -L 1 -E;
  • E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R 2 ; and
  • L 1 is —NH— or —CH 2 —NH—, wherein the group —CH 2 —NH— is linked to ring A through the N atom and to ring E through the —CH 2 — group.
  • each R 1 is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, O-carboxy, C-carboxy, carbamate and urea.
  • R 1 is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, O-carboxy
  • each R 1 is independently selected from C 1-8 alkyl, cyclyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl
  • each R 2 is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, O-carboxy, C-carboxy, carbamate and urea.
  • R 2 When there is more than one R 2 as a substituent on ring E, they can be the same or different.
  • each R 2 is independently selected from C 1-8 alkyl, cyclyl, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide and C 1-8 , alkoxy. In another embodiment, each R 2 is independently selected from C 1-8 alkyl, cyclyl, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, N-sulfonamido and C 1-8 alkoxy.
  • each R 2 is independently selected from hydroxyl, halo (for example fluoro or chloro), haloC 1-8 alkyl (for example trifluoromethyl) and sulfonamide (preferably N-sulfonamido). In another embodiment, each R 2 is independently selected from hydroxyl, halo, haloC 1-8 alkyl and N-sulfonamido.
  • each R 2 is independently selected from hydroxyl, halo, haloC 1-8 alkyl and —NR′SO 2 R (wherein R and R′ are as defined herein below; preferably R′ is H and R is C 1-8 alkyl (for example, methyl, ethyl or isopropyl) or R′ is H and R is optionally substituted phenyl).
  • each R 2 is independently selected from hydroxyl, halo and haloC 1-8 alkyl.
  • each R 2 is independently selected from hydroxyl, halo and haloC 1-4 alkyl.
  • each R 2 is independently selected from hydroxyl, chloro, fluoro or trifluoromethyl.
  • ring E is substituted with one R 2 and said R 2 is N-sulfonamido, i.e. —NR′SO 2 R (wherein R and R′ are as defined herein below; preferably R′ is H and R is C 1-8 alkyl (for example, methyl, ethyl or isopropyl) or R′ is H and R is optionally substituted phenyl).
  • R and R′ are as defined herein below; preferably R′ is H and R is C 1-8 alkyl (for example, methyl, ethyl or isopropyl) or R′ is H and R is optionally substituted phenyl).
  • Ia, Ia-1, Ib or Ic, L 2 and D have the following meanings:
  • L 2 is a bond and D is a cyclic group selected from:
  • D can thus be a monocyclic ring (group i) or polycyclic ring (group ii).
  • “Polycyclic ring system” as used herein means a ring system containing 2 or more rings, preferably containing two (i.e. bicyclic) or three (i.e. tricyclic) rings, which rings can be fused, bridged or spiro rings, or any combination thereof.
  • tricyclic rings include for example three fused rings, or two rings fused together, one of which is a spiro bicyclic ring.
  • a fused ring as used herein means that two rings are linked to each other through two adjacent ring atoms common to both rings.
  • a bridged ring as used herein means that a ring comprises a linker group —(C(R a ) 2 ) p — linking together any two non-adjacent carbon or nitrogen atoms of the ring, wherein p is 1 or 2 and each R a independently is hydrogen or C 1-4 alkyl.
  • a spiro ring as used herein means two rings linked together via a single carbon atom common to both rings.
  • Ring D can contain 1 or 2 heteroatoms independently selected from N, O and S in case of cyclic group (i) or from 1 to 4 heteroatoms independently selected from N, O and S in case of cyclic group (ii).
  • D contains 1 or 2 heteroatoms independently selected from N, O and S in case of cyclic group (i) or from 1 to 4 heteroatoms independently selected from N, O and S in case of cyclic group (ii), wherein ring D contains at least 1 N atom.
  • cyclic group (i) contains 1 heteroatom selected from N, O and S.
  • cyclic group (i) contains 1 N atom.
  • cyclic group (ii) contains 1 or 2 heteroatoms independently selected from N, O and S.
  • cyclic group (ii) contains 1 or 2 N atoms.
  • Cyclic group (ii) as defined above refers to a 7- to 15-membered polycyclic ring system which comprises at least one saturated heterocyclic ring.
  • One ring forming part of cyclic group (ii) must thus be a saturated heterocyclic ring, while the other ring(s) can be saturated, partially unsaturated or aromatic carbocyclic or heterocyclic rings.
  • cyclic group (ii) is a saturated polycyclic ring system, i.e. all rings forming cyclic group (ii) are saturated.
  • D (i.e. groups (i) or (ii)) is linked to the remainder of the compound of Formula I through a ring C atom.
  • the C atom linking D to the remainder of the compound of formula I can be in any of the rings and thus can be in the saturated heterocyclic ring or any other ring forming part of cyclic group (ii).
  • D i.e. cyclic group (i) or (ii)
  • may be optionally substituted with one or more R 3 which can be the same or different and may be placed at any available carbon or nitrogen atom of cyclic group (i) or of any of the rings of cyclic group (ii).
  • the substituent(s) R 3 if present, are placed on ring C atom(s).
  • D is not substituted with any R 3 .
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and visa cyclic group selected from:
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and D is a cyclic group selected from:
  • L 2 is a bond and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S,
  • L 2 is a bond and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O and S,
  • L 2 is a bond and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N, O and S,
  • L 2 is a bond and D is a 6-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N, O and S,
  • L 2 is a bond and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 N atom,
  • L 2 is a bond and D is piperidinyl
  • L 2 is a bond and D is piperidinyl, wherein said piperidinyl is linked to the remainder of the compound of Formula I through a ring C atom, and
  • L 2 is a bond and D is piperidinyl, wherein said piperidinyl is linked to the remainder of the compound of Formula I through a ring C atom, and
  • L 2 is a bond and D is 4-piperidinyl optionally substituted with one or more R 3 .
  • L 2 is a bond and D is 4-piperidinyl optionally substituted with one or more R 3 , wherein said substituent(s) R 3 , if present, are placed on C atom(s) of said piperidine ring.
  • L 2 is a bond and D is 4-piperidinyl.
  • L 2 is a bond and D is a group of the following formula:
  • L 2 is a bond and D is a 7- to 15-membered polycyclic ring system which comprises at least one saturated heterocyclic ring, wherein the polycyclic ring system contains from 1 to 4 heteroatoms independently selected from N, O and S,
  • L 2 is a bond and D is a 7- to 15-membered saturated polycyclic ring system which comprises at least one heterocyclic ring, wherein the polycyclic ring system contains from 1 to 4 heteroatoms independently selected from N, O and S,
  • L 2 is a bond and D is a 7- to 15-membered saturated polycyclic ring system which comprises at least one heterocyclic ring, wherein the polycyclic ring system contains 1 or 2 N atoms,
  • L 2 is a bond and D is a 7- to 15-membered saturated polycyclic ring system selected from a group of formula (a), (b), (c) and (d)
  • D is optionally substituted with one or more R 3 .
  • Said substituent(s) R 3 if present, can be placed on any available position, including on the N atom.
  • L 2 is a bond and D is a 7- to 15-membered saturated polycyclic ring system selected from a group of formula (a), (b) and (c)
  • D is optionally substituted with one or more R 3 .
  • Said substituent(s) R 3 if present, can be placed on any available position, including on the N atom.
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 —CH 2 —) and D is a cyclic group selected from:
  • D can thus be a monocyclic saturated ring (group iii) or polycyclic saturated ring (group iv).
  • “Polycyclic saturated ring system” as used herein means a ring system containing 2 or more saturated rings, preferably containing two (i.e. bicyclic) or three (i.e. tricyclic) saturated rings, which rings can be fused, bridged or spiro rings, or any combination thereof.
  • tricyclic rings include for example three fused rings, or two rings fused together, one of which is a spiro bicyclic ring.
  • a fused ring as used herein means that two rings are linked to each other through two adjacent ring atoms common to both rings.
  • a bridged ring as used herein means that a ring comprises a linker group —(C(R a ) 2 ) p — linking together any two non-adjacent carbon or nitrogen atoms of the ring, wherein p is 1 or 2 and each R a independently is hydrogen or C 1-4 alkyl.
  • a Spiro ring as used herein means two rings linked together via a single carbon atom common to both rings.
  • Ring D can contain 1 or 2 heteroatoms independently selected from N, O and S in case of cyclic group (iii) or from 1 to 4 heteroatoms independently selected from N, O and S in case of cyclic group (iv).
  • D contains 1 or 2 heteroatoms independently selected from N, O and S in case of cyclic group (iii) or from 1 to 4 heteroatoms independently selected from N, O and S in case of cyclic group (iv), wherein ring D contains at least 1 N atom.
  • cyclic group (iii) contains 1 heteroatom selected from N, O and S.
  • cyclic group (iv) contains 1 N atom.
  • cyclic group (iii) contains 1 or 2 heteroatoms independently selected from N, O and S.
  • cyclic group (iv) contains 1 or 2 N atoms.
  • Cyclic group (iv) as defined above refers to a 7- to 15-membered polycyclic saturated ring system which comprises at least one heterocyclic ring.
  • One ring forming part of cyclic group (iv) must thus be a saturated heterocyclic ring, while the other ring(s) can be saturated carbocyclic or heterocyclic rings.
  • D (i.e. groups (iii) or (iv)) is linked to the remainder of the compound of Formula I through a ring C atom.
  • the C atom linking D to the remainder of the compound of formula I can be in any of the rings and thus can be in the saturated heterocyclic ring or any other (carbocyclic or heterocyclic) saturated ring forming part of cyclic group (iv).
  • D i.e. cyclic group (iii) or (iv)
  • may be optionally substituted with one or more R 3 which can be the same or different and may be placed at any available carbon or nitrogen atom of cyclic group (iii) or of any of the rings of cyclic group (iv).
  • the substituent(s) R 3 if present, are placed on ring C atom(s).
  • D is not substituted with any R 3 .
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a cyclic group selected from:
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a cyclic group selected from:
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a cyclic group selected from:
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a cyclic group selected from:
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a cyclic group selected from:
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O and S,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N, O and S,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 6-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N, O and S,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 N atom,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is piperidinyl,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is piperidinyl, wherein said piperidinyl is linked to the remainder of the compound of Formula I through a ring C atom, and
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is piperidinyl, wherein said piperidinyl is linked to the remainder of the compound of Formula I through a ring C atom, and
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is 4-piperidinyl optionally substituted with one or more R 3 .
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is 4-piperidinyl optionally substituted with one or more R 3 , wherein said substituent(s) R 3 , if present, are placed on atom(s) of said piperidine ring.
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is 4-piperidinyl.
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a group of the following formula:
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is azetidinyl, wherein said azetidinyl is linked to the remainder of the compound of Formula I through a ring C atom, and
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is 3-azetidinyl optionally substituted with one or more R 3 .
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 7- to 15-membered polycyclic saturated ring system which comprises at least one heterocyclic ring,
  • polycyclic saturated ring system contains from 1 to 4 heteroatoms independently selected from N, O and S,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 7- to 15-membered saturated polycyclic ring system which comprises at least one heterocyclic ring,
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 7- to 15-membered saturated polycyclic ring system selected from a group of formula (a), (b), (c) and (d)
  • D is optionally substituted with one or more R 3 .
  • Said substituent(s) R 3 if present, can be placed on any available position, including on the N atom.
  • L 2 is C 1-4 alkylene (preferably linear C 1-4 alkylene, more preferably —CH 2 — or —CH 2 CH 2 —) and D is a 7- to 15-membered saturated polycyclic ring system selected from a group of formula (a), (b) and (c)
  • D is optionally substituted with one or more R 3 .
  • Said substituent(s) R 3 if present, can be placed on any available position, including on the N atom.
  • each R 3 is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, O-carboxy, C-carboxy, carbamate and urea.
  • each R 3 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, nitro, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonyl, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, O-carboxy, C-carboxy, carbamate and urea.
  • each R 3 is independently selected from C 1-8 alkyl, halo, C 1-8 alkoxy, hydroxyl, amino, and amido.
  • each R 3 is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I (including a compound Ia, Ib or Ic) wherein the groups -A-B and —NH-L 2 -D are in trans configuration.
  • the invention provides a compound of formula Ia wherein the groups -A-B and —NH-L 2 -D are in trans configuration, which is a compound of formula Ia-1:
  • the invention provides a compound of formula I wherein each R w , R x , R y and R z is independently selected from hydrogen, fluoro and C 1-4 alkyl, preferably from hydrogen, fluoro and methyl.
  • the invention provides a compound of formula I wherein each R w , R x , R y and R z is independently selected from hydrogen and fluoro.
  • the invention provides a compound of formula I wherein R w is fluoro and each R x , R y and R z is independently selected from hydrogen, halo and C 1-4 alkyl; preferably, R w is fluoro and each R x , R y and R z is hydrogen.
  • the invention provides a compound of formula I wherein R z is fluoro and each R w , R x and R y is independently selected from hydrogen, halo and C 1-4 alkyl; preferably, R z is fluoro and each R w , R x and R y is hydrogen.
  • the invention provides a compound of formula I wherein R w and R z are fluoro and each R x and R y is independently selected from hydrogen, halo and C 1-4 alkyl; preferably, R w and R z are fluoro and each R x and R y is hydrogen.
  • the invention provides a compound of formula I wherein R w is selected from hydrogen, halo and C 1-4 alkyl, preferably from hydrogen, fluoro and methyl, and each R x , R y and R z is hydrogen.
  • the invention provides a compound of formula I wherein each R w , R x , R y and R z is hydrogen, i.e. a compound of formula Ia:
  • the invention provides a compound of formula I wherein each R w , R x , R y and R z is independently selected from hydrogen, halo and C 1-4 alkyl with the proviso that at least one is not hydrogen, i.e. a compound of formula Ib.
  • the invention provides a compound of formula I wherein R w is selected from halo and C 1-4 alkyl, preferably from fluoro and methyl, and each R x , R y and R z is hydrogen, i.e. a compound of formula Ic.
  • R w is methyl.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein L 2 is a bond or linear C 1-4 alkylene, preferably L 2 is a bond or linear C 1-2 alkylene.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein L 2 is a bond.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein L 2 is C 1-4 alkylene, preferably linear C 1-4 alkylene, more preferably linear C 1-2 alkylene.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein L 2 is CH 2 .
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein L 2 is CH 2 CH 2 .
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • D is optionally substituted with one or more R 3 .
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • polycyclic saturated ring system contains from 1 to 4 heteroatoms independently selected from N, O and S,
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • D is optionally substituted with one or more R 3 .
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein A is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl, naphthyl or monocyclic heteroaryl is optionally substituted with one or more (e.g., one or two) R 1 .
  • A is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl, naphthyl or monocyclic heteroaryl is optionally substituted with one or more (e.g., one or two) R 1 .
  • A is phenyl, naphthyl, pyridyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl, wherein A is optionally substituted with one or more R 1 . More preferably, A is phenyl, naphthyl, pyridyl or thiazolyl, wherein A is optionally substituted with one or more R 1 . Still more preferably, A is phenyl, 2-naphthyl, 3-pyridyl or 5-thiazolyl, wherein A is optionally substituted with one or more R 1 . In one embodiment, A is phenyl optionally substituted with one or more R 1 .
  • A is naphthyl, preferably 2-naphthyl, optionally substituted with one or more R 1 .
  • A is pyridyl, preferably 3-pyridyl, optionally substituted with one or more R 1 .
  • A is thiazolyl, preferably 5-thiazolyl, optionally substituted with one or more R 1 .
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein A is phenyl or monocyclic heteroaryl, wherein said phenyl or said monocyclic heteroaryl is optionally substituted with one or more R 1 .
  • A is phenyl, pyridyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl, wherein A is optionally substituted with one or more R 1 .
  • A is phenyl, pyridyl or thiazolyl, wherein A is optionally substituted with one or more R 1 .
  • A is phenyl.
  • A is monocyclic heteroaryl.
  • A is pyridyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl.
  • A is 3-pyridyl.
  • A is 5-thiazolyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein A is phenyl optionally substituted with one or more R 1 .
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein A is naphthyl (e.g. 2-naphthyl) optionally substituted with one or more R 1 .
  • A is naphthyl (e.g. 2-naphthyl) optionally substituted with one or more R 1 .
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein A is heteroaryl optionally substituted with one or more R 1 .
  • A is monocyclic heteroaryl optionally substituted with one or more R 1 .
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoremethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 , alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-6 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 1 is independently selected from C 1-8 alkyl, amino, amido, hydroxyl, halo, haloC 1-8 alkyl, haloC 1-8 alkoxy, cyano, sulfonamide, C 1-8 alkoxy, acyl, carboxyl, carbamate, and urea.
  • each R 1 is independently selected from halo, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), C 1-4 alkoxy (e.g. methoxy) and C 3-6 cycloalkyl (e.g. cyclopropyl).
  • each R 1 is independently selected from halo, C 1-4 alkyl and C 3-8 cycloalkyl.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH—NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group,
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O— wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • said substituent(s) R 3 are placed on ring C atom(s) of cyclic group (i) or (ii).
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1 Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1 and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from —C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amigo.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) wherein:
  • L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • E is phenyl optionally substituted with one or more R 2 and L 1 is a bond, —O—, —NH—, —CH 2 —NH—, or —CH 2 —O—, wherein said —CH 2 —NH— or —CH 2 —O— groups are linked to ring A through the N or O atom, respectively, and are linked to ring E through the —CH 2 — group.
  • L 1 is a bond or —CH 2 —O—, wherein said —CH 2 —O— group is linked to ring A through the O atom and to ring E through the —CH 2 — group.
  • each R 3 if present, is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, hydroxyl, amino, and amido.
  • the invention provides a compound of formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) selected from:
  • the invention provides the following compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1), in which L 2 is a bond:
  • the invention further provides the following compounds of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1), in which L 2 is C 1-4 alkylene:
  • the invention provides a compound of formula I selected from:
  • the present invention furthermore provides a compound of formula I selected from:
  • the invention also relates to any one or any subgroup of the compounds listed above.
  • the invention likewise relates to a pharmaceutically acceptable salt, preferably a hydrochloride salt (such as, e.g., a monohydrochloride salt, a dihydrochloride salt or, where applicable, a trihydrochloride salt), of any of the compounds listed above.
  • a pharmaceutically acceptable salt preferably a hydrochloride salt (such as, e.g., a monohydrochloride salt, a dihydrochloride salt or, where applicable, a trihydrochloride salt), of any of the compounds listed above.
  • the compound of Formula I, Ia or Ia-1 is not 1-methyl-N-(2-phenylcyclopropyl)-4-piperidinamine or a salt or solvate thereof. Accordingly, in all of the embodiments described herein, the compound Formula I, Ia or Ia-1 for use as a medicament as well as for use in the treatment or prevention of cancer, a neurological disease or a viral infection is preferably not 1-methyl-N-(2-phenylcyclopropyl)-4-piperidinamine or a salt or solvate thereof.
  • Preferred embodiments of the compounds of Formula I, Ia, Ia-1, Ib and Ic for use in the compositions and methods of the invention are as defined herein above.
  • the present invention also provides compounds of Formula I, Ia or Ia-1, as defined and described herein above, including also compounds as defined in any of the preferred embodiments of Formula I, Ia or Ia-1 described herein, with the proviso that the following compounds are excluded:
  • the invention relates to a compound of Formula I, Ia or Ia-1, as defined and described herein above, including also compounds as defined in any of the preferred embodiments of Formula I, Ia or Ia-1 described herein, with the proviso that the following compounds are excluded:
  • the present invention further provides compounds of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1), as defined and described herein above, including also compounds as defined in any of the preferred embodiments of Formula I, Ia, Ia-1, Ib or Ic described herein, in which (i) A is aryl optionally substituted with one or more R 1 and B is -L 1 -E, or (ii) A is heteroaryl optionally substituted with one or more R 1 and B is H, R 1 or -L 1 -E.
  • A is aryl optionally substituted with one or more R 1 and B is -L 1 -E
  • A is heteroaryl optionally substituted with one or more R 1 and B is H, R 1 or -L 1 -E.
  • the present invention furthermore provides compounds of Formula I, Ia, Ib or Ic (preferably a compound of formula I or Ia, more preferably a compound of formula Ia), as defined and described herein above, including also compounds as defined in any of the preferred embodiments of Formula I, Ia, Ia-1, Ib or Ic described herein, in which the substituents -A-B and —NH-L 2 -D on the cyclopropyl moiety are in trans-configuration.
  • compounds of Formula I, Ia, Ib or Ic preferably a compound of formula I or Ia, more preferably a compound of formula Ia
  • the present invention also provides compounds of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1), as defined and described herein above, including also compounds as defined in any of the preferred embodiments of Formula I, Ia, Ia-1, Ib or Ic described herein, in which the compound of formula I, Ia, Ia-1, Ib or Ic is an optically active stereoisomer.
  • the invention relates to compounds which are cyclopropylamino derivatives, so that cyclopropylimino compounds are not covered. Accordingly, compounds such as, e.g., (S,Z)—N-(2,3-dichlorophenyl)-3-oxo-1-(((1S,2R)-2-phenylcyclopropyl)imino)tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxamide, (S,Z)-tert-butyl 3-oxo-1-(((1S,2R)-2-phenylcyclopropyl)imino)tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate or 3H-Oxazolo[3,4-a]pyrazin-3-one, hexahydro-1-[[(1S,2R)-2-phenylcyclopropy
  • the invention provides a method for identifying a compound which is a selective inhibitor of LSD1, the method comprising selecting or providing a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) and determining the ability of the said compound to inhibit LSD1 and MAO-A and/or MAO-B using assays such as the ones disclosed in more detail later on, wherein a compound that inhibits LSD1 to a greater extent than MAO-A and/or MAO-B is identified as a LSD1 selective inhibitor.
  • LSD1 selective inhibitors have IC50 values for LSD1 which are lower than the IC50 value for MAO-A and/or MAO-B.
  • the IC50 values for LSD1 are two-fold lower than for MAO-A and/or MAO-B.
  • the LSD1 IC50 value is at least 5-fold lower than the IC50 value for MAO-A and/or MAO-B.
  • the LSD1 IC50 value is at least 10-fold lower than the IC50 value for MAO-A and/or MAO-B.
  • a selective LSD1 inhibitor exhibits an IC50 value for LSD1 that is >50-fold, preferably >100-fold lower than the IC50 value for MAO-A and/or MAO-B.
  • Individual stereoisomers of compounds of the invention can be prepared synthetically from commercially available chiral starting materials or by separation from mixtures of stereoisomers, as also shown in the Examples.
  • mixtures of diastereomers can be separated by conventional separation techniques such as recrystallization or chromatography.
  • Mixtures of enantiomeric products can be separated by conversion to a mixture of diastereomers followed by separation using recrystallization or chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method of chiral resolution known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E
  • Z
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E
  • Z
  • the mixtures thereof may exist as geometric isomers.
  • the compounds of the invention contain one or more basic nitrogen atoms and may therefore form salts with organic or inorganic acids.
  • the compounds of the invention may also contain one or more acidic protons and therefore they may also form salts with bases.
  • the salts of a compound of the invention can be obtained during the final isolation and purification of the compounds of the invention or can be obtained by treating a compound of formula I, Ia, Ia-1, Ib or Ic with a sufficient amount of the desired acid or base to give the corresponding salt in a conventional manner.
  • a compound of formula I, Ia, Ia-1, Ib or Ic is provided in the form of a salt.
  • a compound of formula I, Ia, Ia-1, Ib or Ic is provided in the form of a pharmaceutically acceptable salt.
  • such pharmaceutically acceptable salt is a hydrochloride, for example a monohydrochloride, a dihydrochloride or a trihydrochloride.
  • the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms with water are known as hydrates. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • the invention thus relates to the unsolvated and solvated forms of the compounds of formula I, Ia, Ia-1, Ib or Ic (or of any salt thereof).
  • the compounds of formula I, Ia, Ia-1, Ib and Ic may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of the invention, including all polymorphic forms (also known as polymorphs) thereof, are included within the scope of the invention.
  • the present invention further covers all unlabeled and isotopically labeled forms of the compounds of formula I, Ia, Ia-1, Ib and Ic.
  • the invention relates to deuterated forms of the compounds of formula I, Ia and Ia-1.
  • the invention also relates to a compound of Formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and most preferably a compound of formula Ia-1) as described and defined herein, wherein the substituents -A-B and —NH-L 2 -D on the cyclopropyl moiety are in trans-configuration and further wherein the compound is optically active.
  • the term “optically active,” refers to the ability of a compound to rotate plane polarized light.
  • the invention in another aspect, relates to a substantially pure, optically active stereoisomer of a compound of Formula I, Ia, Ia-1 Ib or Ic as described and defined herein, wherein the substituents -A-B and —NH-L 2 -D on the cyclopropyl moiety are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, as well as its use as a medicament.
  • substantially pure means that there is 90 mole-% or greater of the desired stereoisomer and 10 mole-% or less of any other stereoisomer, preferably that there is 95 mole-% or greater of the desired stereoisomer and 5 mole-% or less of any other stereoisomer, more preferably, that there is 98 mole-% or greater of the desired stereoisomer and 2 mole-% or less of any other stereoisomer, still more preferably, that there is 99 mole-% or greater of the desired stereoisomer and 1 mole-% or less of any other stereoisomer, and even more preferably that there is 99.5 mole-% or greater of the desired stereoisomer and 0.5 mole-% or less of any other stereoisomer.
  • the substantially pure, optically active stereoisomer of a compound of Formula I, Ia, Ia-1, Ib or Ic as described and defined herein, wherein the substituents -A-B and —NH-L 2 -D on the cyclopropyl moiety are in trans-configuration, is useful in treating or preventing a disease or disorder, particularly cancer, a neurological disease, or a viral infection.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other moiety where the atom attached to the carbonyl is carbon.
  • acyl refers to a group of formula —C( ⁇ O)R′′, wherein R′′ represents alkenyl, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl.
  • An “acetyl” group refers to a —C( ⁇ O)CH 3 group.
  • alkylcarbonyl or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylcarbonyl or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • examples of such groups include, but are not limited to, methylcarbonyl or ethylcarbonyl.
  • acyl groups include, but are not limited to, formyl, alkanoyl or aroyl.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms.
  • a C 2-8 alkenyl is an alkenyl group having from 2 to 8 carbon atoms.
  • alkoxy refers to an alkyl ether group (ie a group of formula alkyl-O—), wherein the term alkyl is as defined below.
  • suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or n-pentoxy.
  • C 1-z alkoxy refers to an alkoxy group wherein the alkyl moiety has from 1 to z carbon atoms; for example a C 1-8 alkoxy is an alkoxy group wherein the alkyl moiety is C 1-8 alkyl, i.e. a group of formula C 1-8 alkyl-O—.
  • alkyl refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms.
  • a C 1-z alkyl is an alkyl from 1 to z carbon atoms; thus, a C 1-8 alkyl has from 1 to 8 carbon atoms, a C 1-4 alkyl has from 1 to 4 carbon atoms and a C 1-2 alkyl has from 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, iso-amyl, hexyl, heptyl, octyl, or nonyl.
  • C 1-4 alkylene refers to an C 1-4 alkyl group attached at two positions, i.e. an alkanediyl group. Examples include, but are not limited to, methylene, ethylene, propylene and butylene. Accordingly, the term “C 1-4 alkylene” may refer to a straight-chain or branched-chain alkylene group having from 1 to 4 carbon atoms.
  • a “linear C 1-4 alkylene” refers to a straight chain alkylene group having from 1 to 4 carbon atoms, i.e. a —(CH 2 ) y ⁇ group wherein y is 1, 2, 3 or 4.
  • alkynyl refers to a straight-chain or branched-chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms.
  • a C 2-8 alkynyl has from 2 to 8 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl.
  • amido refers to an amino group as described below attached to the parent molecular moiety through a carbonyl group (e.g., —C( ⁇ O)NRR′), or vice versa (—N(R)C( ⁇ O)R′).
  • Amido encompasses “C-amido” and “N-amido” as defined herein. R and R′ are as defined herein.
  • C-amido refers to a —C( ⁇ O)NRR′ group with R and R′ as defined herein.
  • N-amido refers to a —N(R)C( ⁇ O)R′ group with R and R′ as defined herein.
  • amino refers to —NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclyl, and heterocyclyl. Additionally, R and R′ may be combined to form a heterocyclyl.
  • exemplary “amino” groups include, without being limited thereto, —NH 2 , —NH(C 1-4 alkyl) and —N(C 1-4 alkyl)(C 1-4 alkyl).
  • aryl refers to a carbocyclic aromatic system containing one ring, or two or three rings fused together where in the ring atoms are all carbon.
  • aryl groups includes, but is not limited to groups such as phenyl, naphthyl, or anthracenyl.
  • monocyclic aryl refers to phenyl.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy (—O—).
  • carbamate refers to an O-carbamyl or N-carbamyl group as defined herein.
  • An N-carbamyl group refers to —NR—COOR′, wherein R and R′ are as defined herein.
  • An O-carbamyl group refers to —COC—NRR′, wherein R and R′ are as defined herein.
  • carbonyl when alone includes formyl —C( ⁇ O)H and in combination is a —C( ⁇ O)— group.
  • carboxyl or “carboxy” refers to —C( ⁇ O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
  • O-carboxy refers to a RC( ⁇ O)O— group, where R is as defined herein.
  • C-carboxy refers to a —C( ⁇ O)OR groups where R is as defined herein.
  • cyano refers to —CN
  • Carbocyclyl refers to a saturated or partially saturated monocyclic or a fused bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. “Carbocyclyl” encompasses benzo fused to a carbocyclyl ring system. One group of carbocyclyls have from 5 to 7 carbon atoms.
  • carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, or adamantyl.
  • cycloalkyl refers to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members.
  • a C 3-6 cycloalkyl is a cycloalkyl that has from 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.
  • cyclyl refers to an aryl, heterocyclyl, or carbocyclyl group as defined herein.
  • halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • haloalkoxy refers to a haloalkyl group (as defined below) attached to the parent molecular moiety through an oxygen atom.
  • a haloC 1-8 alkoxy group refers to a haloalkoxy group wherein the haloalkyl moiety has from 1 to 8 C atoms.
  • Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy, or 3-chloropropoxy.
  • haloalkyl refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen.
  • a haloC 1-8 alkyl group refers to a haloalkyl group wherein the alkyl moiety has from 1 to 8 C atoms.
  • monohaloalkyl, dihaloalkyl or polyhaloalkyl groups may have an iodo, bromo, chloro or fluoro atom within the group.
  • Dihalo or polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl or dichloropropyl.
  • heteroalkyl refers to a straight or branched alkyl chain, wherein one, two, or three carbons forming the alkyl chain are each replaced by a heteroatom independently selected from the group consisting of O, N, and S, and wherein the nitrogen and/or sulfur heteroatom(s) (if present) may optionally be oxidized and the nitrogen heteroatom(s) (if present) may optionally be quaternized.
  • the heteroatom(s) O, N and S may, for example, be placed at the end(s) or at an interior position of the heteroalkyl group, i.e., the heteroalkyl may be bound to the remainder of the molecule via a heteroatom or a carbon atom.
  • heteroalkyl Up to two heteroatoms may be consecutive, such as, for example, —CH 2 —NH—OCH 3 .
  • a further example for a “heteroalkyl” group is a straight or branched alkyl group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., —S( ⁇ O) 2 —NH 2 , —S( ⁇ O) 2 —NH(alkyl) or —S( ⁇ O) 2 —N(alkyl)(alkyl).
  • heteroC 1-4 alkylene refers to a straight or branched C 1-4 alkylene group (i.e., a straight or branched C 1-4 alkanediyl group) linked to one heteroatom selected from O, N and S and also refers to a straight or branched C 1-4 alkylene group wherein one or more (e.g., 1, 2 (if present) or 3 (if present)) of the carbon atoms of said alkylene group are each replaced by a heteroatom independently selected from O, N or S.
  • the nitrogen and/or sulfur heteroatom(s) (if present) may optionally be oxidized and the nitrogen heteroatom(s) (if present) may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at the end(s) and/or at an interior position of the heteroC 1-4 alkylene group. It is to be understood that the presence of hydrogen atoms will depend on the valence of the heteroatom replacing the respective carbon atom. If, for example, the carbon atom in a —CH 2 — group is replaced by O or S, the resulting group will be —O— or —S—, respectively, while it will be —N(H)— when the carbon atom is replaced by N.
  • a “heteroC 1-4 alkylene” group is a straight or branched C 1-4 alkylene group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., —S( ⁇ O) 2 —N(H)— or —S( ⁇ O) 2 —N(CH 3 )—.
  • heteroaryl refers to a 5 to 6 membered unsaturated monocyclic ring, or a fused bicyclic or tricyclic ring system in which the rings are aromatic and in which at least one ring contains at least one heteroatom selected from the group consisting of O, S, and N.
  • Preferred heteroaryl groups are 5- to 6-membered monocyclic or 9- to 10-membered bicyclic heteroaryl groups.
  • heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazan
  • heterocyclyl or “heterocycle” or “heterocyclic ring” each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each of said at least one heteroatoms may be independently selected from the group consisting of nitrogen, oxygen, and sulfur wherein the nitrogen or sulfur atoms may be oxidized (e.g., —N ⁇ O, —S( ⁇ O)—, or —S( ⁇ O) 2 —).
  • 1, 2, or 3 of the carbon atoms of the heterocyclyl may be optionally oxidized (e.g., to give an oxo group or ⁇ O).
  • One group of heterocyclyls has from 1 to 4 heteroatoms as ring members.
  • Another group of heterocyclyls has from 1 to 2 heteroatoms as ring members.
  • One group of heterocyclyls has from 3 to 8 ring members in each ring.
  • Yet another group of heterocyclyls has from 3 to 7 ring members in each ring.
  • Another group of heterocyclyls has from 5 to 6 ring members in each ring.
  • “Heterocyclyl” is intended to encompass a heterocyclyl group fused to a carbocyclyl or benzo ring systems.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiola
  • heteroaryls that are heterocyclyls include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazany
  • heterocycloalkyl refers to a heterocyclyl group that is not fully unsaturated e.g., one or more of the rings systems of a heterocycloalkyl is not aromatic.
  • heterocycloalkyls include piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.
  • hydroxyl or “hydroxy” refers to —OH.
  • the term “lower” where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.
  • nitro refers to —NO 2 .
  • the term “saturated” in relation to a ring means that the ring does not contain any unsaturation.
  • sulfonate As used herein, the terms “sulfonate” “sulfonic acid” and “sulfonic” refer to the —SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • sulfinyl refers to —S( ⁇ O)(R), with R as defined herein.
  • sulfonyl refers to —S( ⁇ O) 2 R, with R as defined herein.
  • sulfonamide refers to an N-sulfonamido or S-sulfonamido group as defined herein.
  • N-sulfonamido refers to a RS( ⁇ O) 2 N(R′)— group with R and R′ as defined herein.
  • exemplary, non-limiting N-sulfonamido groups are —NHSO 2 alkyl such as —NHSO 2 CH 3 , —NHSO 2 CH 2 CH 3 or —NHSO 2 (isopropyl), and —NHSO 2 (optionally substituted aryl) such as —NHSO 2 phenyl —NHSO 2 -(2-cyanophenyl), —NHSO 2 -(3-cyanophenyl), —NHSO 2 -(4-cyanophenyl), —NHSO 2 -(2-aminophenyl), —NHSO 2 -(3-aminophenyl) or —NHSO 2 -(4-aminophenyl).
  • S-sulfonamido refers to a —S( ⁇ O) 2 NRR′, group, with R and R′ as defined herein.
  • urea refers to a —N(R)C( ⁇ O)N(R)(R′) group wherein R and R′ are as defined herein.
  • R or the term R′ appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl.
  • every substituent, and every term should be understood to be independent of every other in terms of selection from a group.
  • any variable, substituent, or term e.g., aryl, heterocycle, R, etc.
  • its definition at each occurrence is independent of the definition at every other occurrence.
  • certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written.
  • an unsymmetrical group such as —C( ⁇ O)N(R)— may be attached to the parent moiety at either the carbon or the nitrogen.
  • the term “optionally substituted” means the preceding or anteceding group may be substituted or unsubstituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, heteroaryl, pyridyl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, halogen, hydroxyl, amino, amido, nitro, thiol, lower alkylthio,
  • Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., —CH 2 CH 3 ), fully substituted (e.g., —CF 2 CF 3 ), monosubstituted (e.g., —CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH 2 CF 3 ).
  • substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.” In one specific definition, the optional substituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, —N(C 1-3 alkyl) 2 , —NH(C 1-3 alkyl), —NHC( ⁇ O)(C 1-3 alkyl), —C( ⁇ O)OH, —C( ⁇ O)O(C 1-3 alkyl), —C( ⁇ O)(C 1-3 alkyl), —C( ⁇ O)NH 2 , —C( ⁇ O)NH(C 1-3 alkyl), —C( ⁇
  • optional substituent denotes that the corresponding substituent may be present or may be absent. Accordingly, a compound having 1, 2 or 3 optional substituents may be unsubstituted or may be substituted with 1, 2 or 3 substituents.
  • treating a disease refers to a slowing of or a reversal of the progress of the disease. Treating a disease includes treating a symptom and/or reducing the symptoms of the disease.
  • preventing a disease refers to a slowing of the disease or of the onset of the disease or the symptoms thereof. Preventing a disease or disorder can include stopping the onset of the disease or symptoms thereof.
  • the term “dosage unit” refers to a physically discrete unit, such as a capsule or tablet suitable as a unitary dosage for a human patient. Each unit contains a predetermined quantity of a compound of Formula I which was discovered or believed to produce the desired pharmacokinetic profile which yields the desired therapeutic effect.
  • the dosage unit is composed of a compound of Formula I in association with at least one pharmaceutically acceptable carrier, salt, excipient, or combination thereof.
  • the term “subject” or “patient” or “individual”, such as the subject in need of treatment or prevention, may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g.
  • a horse a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
  • a simian e.g., a monkey or ape
  • a monkey e.g., a marmoset, a baboon
  • an ape e.g., gorilla, chimpanzee, orangutang, gibbon
  • a human e.g., gorilla, chimpanzee, orangutang, gibbon
  • Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches. Non-limiting examples of agronomically important animals are sheep, cattle and pig, while, for example, cats and dogs may be considered as economically important animals.
  • the subject/patient/individual is a mammal; more preferably, the subject/patient/individual is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutang, a gibbon, a sheep, cattle, or a pig); even more preferably, the subject/patient/individual is a human.
  • a non-human mammal such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a
  • a 40 mg dose of a compound of Formula I refers to, in the case of a twice-daily dosage regimen, a situation where the individual takes 40 mg of a compound of Formula I twice a day, e.g., 40 mg in the morning and 40 mg in the evening.
  • the 40 mg of a compound of Formula I dose can be divided into two or more dosage units, e.g., two 20 mg dosage units of a compound of Formula I in tablet form or two 20 mg dosage units of a compound of Formula I in capsule form.
  • a therapeutically effective amount refers to the amount sufficient to produce a desired biological effect (e.g., a therapeutic effect) in a subject.
  • a therapeutically effective amount of a compound may be an amount which is sufficient to treat or prevent a disease or disorder, and/or delay the onset or progression of a disease or disorder, and/or alleviate one or more symptoms of the disease or disorder, when administered to a subject suffering from or susceptible to that disease or disorder.
  • a “pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • a “pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, such as hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, me
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.
  • suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.
  • Pharmaceutically acceptable salts are well known in the art.
  • a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to a non-API (API refers to Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.
  • the compounds of the invention are unexpectedly potent and selective inhibitors of LSD1. Avoiding inhibition of “off-targets” can avoid unwanted or undesirable side-effects like the cheese effect associated with MAO-A.
  • the compounds of the invention are thus useful for the treatment or prevention of any disease or disorder associated with LSD1. This includes cancer, neurological diseases and viral infections, among others.
  • the compounds of formula I including compounds of formula Ia, Ia-1, Ib and Ic, as well as any salts and solvates thereof, are used for the treatment or prevention of cancer, and most preferably for the treatment of cancer.
  • Cancers that may be treated (or prevented) with the compounds of the invention include, but are not limited to cancers such as:
  • the compounds of the invention are used for the treatment or prevention of cancer, particularly for the treatment of cancer, wherein said cancer is chosen from blood cancer, leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, neuroblastoma, bladder cancer, liver cancer, sarcoma, myeloma and skin cancer.
  • the compounds of the invention are used for the treatment or prevention (particularly for the treatment) of blood cancers (also known as hematological cancers), including leukemias (for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphomas and myelomas, prostate cancer, breast cancer, lung cancer, colorectal cancer, brain cancer or skin cancer.
  • leukemias for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia
  • lymphomas and myelomas prostate cancer, breast cancer,
  • the compounds of formula I are used for the treatment of a blood cancer. More preferably, the compounds of formula I, including compounds of formula Ia, Ia-1, Ib and Ic, are used for the treatment of leukemia, including acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and hairy cell leukemia.
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • CML chronic neutrophilic leukemia
  • chronic eosinophilic leukemia chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • compounds according to Formula I, Ia, Ia-1, Ib or Ic can be effective at an amount of from about 0.01 ⁇ g/kg to about 100 mg/kg per day based on total body weight.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at predetermined intervals of time.
  • the suitable dosage unit for each administration can be, e.g., from about 1 ⁇ g to about 2000 mg, preferably from about 5 ⁇ g to about 1000 mg. Even more preferably, the amount of active ingredient administered is from about 5 ⁇ g to about 100 mg per day.
  • the therapeutically effective amount for each active compound can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan.
  • the amount of administration can be adjusted as the various factors change over time.
  • a compound of the invention may be administered for use in therapy directly as such, it is typically administered in the form of a pharmaceutical composition, which comprises said compound as active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients or carriers.
  • the compounds of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by the oral, parenteral, intravenous, subcutaneous or topical routes.
  • the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint).
  • binders e.g., gelatin, cellulose, gum tragacanth
  • excipients e.g., starch, lactose
  • lubricants e.g., magnesium stearate, silicon dioxide
  • disintegrating agents e.g., alginate, Primogel, and corn starch
  • sweetening or flavoring agents e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint
  • Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included.
  • the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.
  • the active compounds can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • Topical administration examples include nasal, bucal, mucosal, rectal, or vaginal applications.
  • the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols.
  • one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.
  • a special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference.
  • Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247.
  • Hydrogels can be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. Preferably, hydrogels are biodegradable or biosorbable.
  • hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips et al. (1984) J. Pharmaceut. Sci, 73: 1718-1720.
  • the active compounds can also be conjugated, to a water soluble non-immunogenic non-peptidic high molecular weight polymer to form a polymer conjugate.
  • an active compound is covalently linked to polyethylene glycol to form a conjugate.
  • a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity.
  • the active compound in the conjugate can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp. Pharm. 15:210-218.
  • PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses.
  • PEGylated interferon PEG-INTRON A®
  • PEGylated adenosine deaminase ADAGEN®
  • SCIDS severe combined immunodeficiency disease
  • PEGylated L-asparaginase ONCAPSPAR®
  • ALL acute lymphoblastic leukemia
  • Controlled release of an active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art.
  • Other pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.
  • Liposomes can also be used as carriers for the active compounds of the present invention.
  • Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Pat. No. 4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976).
  • the active compounds can also be administered in combination with another active agent that synergistically treats or prevents the same symptoms or is effective for another disease or symptom in the patient treated so long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention.
  • additional active agents include but are not limited to anti-inflammatory agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, anti-cancer drugs, hypertension drugs, and the like.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each additional active agent in its own separate pharmaceutical dosage formulation. If administered separately, the administration can be simultaneous, sequential or separate, and the compound of the invention and the additional therapeutic agent(s) can be administered via the same administration route or using different administration routes, for example one compound can be administered orally and the other intravenously.
  • a compound of formula I, Ia, Ia-1, Ib or Ic when used for the treatment or prevention of cancer, said compound can be administered in combination with one or more further agents known to be useful in the treatment or prevention of cancer, including chemotherapy or radiotherapy.
  • antineoplastic agent that has activity versus a cancer being treated or prevented with a compound of the invention may be used.
  • antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • antineoplastic agents include the anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynenes and podophyllotoxins.
  • Particularly useful members of those classes include, for example, caminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
  • antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • a compound of formula I, Ia, Ia-1, Ib or Ic can be used for the treatment or prevention of cancer, wherein said compound is to be administered in combination with one or more antineoplastic agents.
  • the antineoplastic agents to be administered for combination therapy may be selected, as appropriate, from: a tumor angiogenesis inhibitor (for example, a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (for example, an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (for example, a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (for example, a nitrogen mustard or a nitrosourea); an endocrine agent (for example, an adrenocorticosteroid, an androgen, an anti
  • An alkylating agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N,N′N′-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine),
  • a platinum coordination complex which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
  • a cytotoxic drug which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).
  • an antimetabolite including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed),
  • An antimitotic agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analog (such as ixabepilone/azaepothilone B).
  • a taxane such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel
  • a Vinca alkaloid such as
  • An anti-tumor antibiotic which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-humor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
  • an anthracycline such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin
  • a tyrosine kinase inhibitor which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, or vandetanib.
  • a topoisomerase-inhibitor which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
  • a topoisomerase I inhibitor such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D
  • a topoisomerase II inhibitor such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin.
  • antineoplastic agents may be used in combination with a compound of the present invention.
  • the antineoplastic agents may include biological or chemical molecules, such as TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, toremifene, fluoxymesterol, raloxifene, diethylstibestrol, bicalutamide, nilutamide, flutamide, aminoglutethimide, anastrozole, tetrazole, luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab,
  • retinoid agents include all natural, recombinant, and synthetic derivatives or mimetics of vitamin A, for example, retinyl palmitate, retinoyl-beta-glucuronide (vitamin A1 beta-glucuronide), retinyl phosphate (vitamin A1 phosphate), retinyl esters, 4-oxoretinol, 4-oxoretinaldehyde, 3-dehydroretinol (vitamin A2), 11-cis-retinal (11-cis-retinaldehyde, 11-cis or neo b vitamin A1 aldehyde), 5,6-epoxyretinol (5,6-epoxy vitamin A1 alcohol), anhydroretinol (anhydro vitamin A1) and 4-ketoretinol (4-keto-vitamin A1 alcohol), all-trans retinoic acid (ATRA; Tretinoin; vitamin A acid; 3,7-dimethyl-9-(
  • lipid formulations of all-trans retinoic acid e.g., ATRA-IV
  • 9-cis retinoic acid (9-cis-RA; Alitretinoin; PanretinTM; LGD1057)
  • 13-cis retinoic acid Isotretinoin
  • Fenretinide N-(4-hydroxyphenyl)retinamide; 4-HPR
  • Etretinate ((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonate
  • histone deacetylase inhibitors include, without limitation, MS-275 (SNDX-275; Entinostat), FK228 (FR901228; depsipeptide; Romidepsin), CI-994 (Acetyldinaline; Tacedinaline), Apicidin (cyclo[(2S)-2-amino-8-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]), A-161906 (7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid), Scriptaid (6-(1,3-Dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxyamide), PXD-101 (Beiinostat), CHAP (cyclic hydroxamic acid-containing peptide), LAQ-824 (Dacinostat), BML
  • biological drugs like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, “full humanized” antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in cancer can be employed in cotherapeutic approaches with the compounds of the invention.
  • Such biological molecules are alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumah, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,
  • biologic agents include, but are not limited to, immunomodulating proteins such as cytokines (such as interleukin-2 (IL-2, Aldesleukin), Epoietin-alpha.; EPO), granulocyte-CSF (G-CSF; Filgrastin), and granulocyte-macrophage-CSF (GM-CSF; Sargramostim) and interferons, (e.g., interferon-alpha, interferon-beta and interferon-gamma), bacillus Calmette-Guerin, levamisole, and octreotide, endostatin, tumor suppressor genes (e.g., DPC4, NF-1, NF-2, RB, p53, WT1, BRCA1, and BRCA2), and cancer vaccines (e.g., tumor associated antigens such as gangliosides (GM2), prostate specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic antigen (
  • the compounds of formula I can be prepared by reductive alkylation of a cyclopropylamino derivative of formula II with a ketone of formula IIIa or and aldehyde of formula IIIb or IIIc, as shown below in Scheme 1:
  • A, B, D, R w , R x , R y , R z and L 2 have the meaning disclosed above in relation to a compound of formula I.
  • Said reductive alkylation can be performed under standard conditions for reductive alkylations, well known in the art.
  • a suitable set of conditions is reacting II with IIIa, IIIb or IIIc using a reducing agent such as a borohydride (e.g. sodium triacetoxyborohydride or sodium borohydride) in a suitable solvent such as dichloroethane or methanol, optionally in the presence of an acid such as acetic acid.
  • a reducing agent such as a borohydride (e.g. sodium triacetoxyborohydride or sodium borohydride)
  • a suitable solvent such as dichloroethane or methanol
  • any other amino group that may be present either in II or in IIIa, IIIb or IIIc be protected using conventional amino-protecting groups to avoid any side reactions; a subsequent deprotection step will be required then if such amino protecting group is present, in order to obtain a compound of formula I.
  • Any suitable amino-protecting group may be used, such as for example a tert-butoxycarbonyl (Boc) group.
  • Boc is used, deprotection can be carried out under standard conditions, for example under acidic conditions using HCl in an organic solvent such as diethyl ether or 1,4-dioxane, or trifluoroacetic acid (TFA) in dichloromethane.
  • TFA trifluoroacetic acid
  • Aldehydes of Formula (1) are subjected to a Horner-Wadsworth-Emmons reaction using triethyl phosphono acetate and a base preferably potassium tert-butoxide in a suitable solvent such as tetrahydrofuran to get the ethyl acrylate derivatives of formula (2) which are then subjected to cyclopropanation reaction using trimethylsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent leading to (trans)-ethyl cyclopropanecarboxylate derivatives of formula (3) (obtained as a trans ((1S,2R) and (1R,2S)) racemic mixture).
  • the (trans)-cyclopropanamine derivatives of formula (12) can be synthesized by reaction of aldehydes of formula (1) with nitromethane and ammonium acetate using tetrahydrofuran as a solvent, leading to the formation of nitrostyrene of formula (10). Later cyclopropanation reaction using trimetilsulfoxonium iodide and potassium tert-butoxide results in the formation of trans nitrocyclopropyl derivatives of formula (11) (obtained as a trans ((1S,2R), (1R,2S)) racemic mixture) and final reduction using zinc in hydrochloric acid affords the (trans)-cyclopropanamine derivatives of formula (12).
  • ketones of formula (13a) or aldehydes of formula (13b) or (13c) containing a protected amino group for example a Boc-protected amine (Boc: tert-Butyloxycarbonyl)
  • an additional deprotection reaction step will be required to render a compound (14a), (14b) or (14c) respectively, which can be performed in acidic conditions, for example using HCl 2M in diethyl ether in a suitable solvent such as diethyl ether, or using HCl in 1,4-dioxane.
  • Aldehydes of formula (1), alkyl halides of formula (7), ketones of formula (13a) and aldehydes of formula (13b) and (13c) are commercially available or can be prepared using well known synthetic procedures starting from readily available starting materials.
  • the (trans)-cyclopropanamine derivatives of formula (26) can be synthesized from aldehydes of formula (16) by conversion into a nitrostyrene of formula (24), subsequent cyclopropanation to give a compound (25) and reduction of the nitro group under the same conditions disclosed in scheme 2 for the conversion of a compound (1) into a compound (12) via compounds (10) and (11).
  • ketones of formula (13a) or aldehydes of formula (13b) or (13c) containing a protected amino group for example a Boc-protected amine (Boc: tert-butoxycarbonyl)
  • an additional deprotection reaction step will be required to render compounds (27a), (27b) or (27c) respectively, which can be performed in acidic conditions, for example using HCl 2M in diethyl ether in a suitable solvent such as diethyl ether or using HCl in 1,4-dioxane.
  • ketones of formula (13a) or aldehydes of formula (13b) or (13c) containing a protected amino group for example a Boc-protected amine (Boc:tert-butoxycarbonyl)
  • an additional deprotection reaction step will be required to render compounds (33a), (33b) or (33c) respectively, which can be performed in acidic conditions, for example using HCl 2M in diethyl ether in a suitable solvent such as diethyl ether or HCl in 1,4-dioxane.
  • the diastereomers can be separated at this point either chromatographically or, after saponification (performed under basic conditions using for example NaOH in a suitable solvent such as MeOH), by recrystallisation of the corresponding carboxylic acids of formula (46).
  • Curtius degradation to Boc-protected cyclopropylamines of formula (47) can be performed by using a base, as for example, triethylamine, diphenylphosphoryl azide and di-tert-butyl dicarbonate in a suitable solvent, as for example, tert-butanol.
  • ketones of formula (13a) or aldehydes of formula (13b) or (13c) containing a protected amino group for example a Boc-protected amine (Boc: tert-Butyloxycarbonyl)
  • an additional deprotection reaction step will be required to render a compound (49a), (49b) or (49c) respectively, which can be performed in acidic conditions, for example using HCl 2M in diethyl ether in a suitable solvent such as diethyl ether or using HCl in 1,4-dioxane.
  • Derivatives of formula (50) are subjected to cyclopropanation using ethyl diazoacetate and copper (I) chloride, as catalyst, in a suitable solvent as chloroform affording to a 1:1 mixtures of cis- and trans-derivatives of formula (51).
  • a suitable solvent as chloroform
  • the copper catalyst disclosed in Scheme 6 can be used.
  • the diastereomers can be separated at this point either chromatographically or, after saponification (performed under basic conditions using for example NaOH in a suitable solvent such as MeOH), by recrystallisation of the corresponding carboxylic acids of formula (52).
  • Curtius degradation to Boc-protected cyclopropylamines of formula (54) can be performed, first by using ethyl chloro formate and a base, as for example, triethylamine in a suitable solvent, as for example, acetone, and subsequent reaction with sodium azide in water leading to cyclopropanecarbonyl azide derivatives of formula (53). Reaction with tert-butanol results in the formation of Boc-protected cyclopropylamines of formula (54).
  • Boc-group in acidic conditions, for example using HCl in 1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl in Et 2 O using Et 2 O as solvent leads to the formation of the cyclopropanamine derivatives of formula (55).
  • ketone of formula (13a) or the aldehydes of formula (13b) or (13c) contain a protected amino group, for example a Boc-protected amine (Boc: tert-butoxycarbonyl)
  • an additional deprotection reaction step will be required to render a compound (56a), (56b) or (56c), which can be performed in acidic conditions, for example using HCl in 1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl in Et 2 O using Et 2 O as solvent.
  • ketones of formula (13a) and the aldehydes of formula (13b) or (13c) are commercially available or can be prepared using well known synthetic procedures starting from readily available starting materials.
  • a suitable solvent such as acetonitrile and water
  • a base such as for example potassium carbonate
  • a palladium catalyst such as tetrakis(triphenylphospine)palladium (0).
  • Boc-group in acidic conditions, for example using HCl 1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl in Et 2 O using Et 2 O as solvent leads to the formation of the (trans)-cyclopropanamine derivatives of formula (61).
  • ketones of formula (13a) or aldehydes of formula (13b) or (13c) contain a protected amino group, for example a Boc-protected amine (Boc: tert-butoxycarbonyl)
  • an additional deprotection reaction step will be required to render a compound (62a), (62b) or (62c).
  • the deprotection can be performed in acidic conditions, for example using HCl-1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl in Et 2 O using Et 2 O as solvent.
  • (trans)-cyclopropylamino derivatives of formula (62a), (62b) or (62c) can be synthesized by reaction of Boc-protected derivatives of formula (39a), (39b) or (39c) with boronic acid or ester derivatives of formula (59) using a suitable solvent such as acetonitrile and water, a base, such as for example potassium carbonate, and a palladium catalyst such as tetrakis(triphenylphospine)palladium(0) affording (trans)-cyclopropanamine derivatives of formula (63a), (63b) or (63c).
  • a suitable solvent such as acetonitrile and water
  • a base such as for example potassium carbonate
  • a palladium catalyst such as tetrakis(triphenylphospine)palladium(0) affording (trans)-cyclopropanamine derivatives of formula (63a), (63b) or (63c).
  • Reaction with boronic acid or ester derivatives of formula (59) using a suitable solvent such as acetonitrile and water, a base, such as for example potassium carbonate, and a palladium catalyst such as tetrakis(triphenylphospine)palladium (0) leads to the formation of compounds of formula (57).
  • Aldehydes of formula (1), boronic acid or ester derivatives of formula (59) and ketones of formula (13a) or aldehydes of formula (13b) or (13c) are commercially available or can be prepared using well known synthetic procedures starting from readily available starting materials.
  • some compounds of the invention can be obtained from other compounds of formula I by appropriate interconversion reactions of functional groups present in a compound of formula I in one or several steps, using well known reactions in organic synthesis under standard experimental conditions.
  • Said transformations can be carried out upon R 1 , R 2 and/or R 3 and may include, for example, the substitution of a primary or secondary amine or of an alcohol by treatment with an alkylating agent, the conversion of an amine into an amide, sulfonamide, carbamate or urea, the palladium-catalyzed cross-coupling of aryl halides with diboranes, boronic acids or esters or with amines, etc.
  • Such interconversion reactions can be performed upon a compound of formula I as well as upon any suitable synthetic intermediate described in the above Schemes.
  • the salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid (or base) to give the salt in a conventional manner.
  • stereoisomers of a compound of formula I can be obtained by separation from a compound of formula I obtained as a mixture of stereoisomers, using well known methods such as formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography.
  • optically pure or enantiomerically enriched synthetic intermediates which can then be used as such in subsequent steps, at various stages of the synthetic procedures described above, using any known method for chiral resolution.
  • the chiral separation is performed upon trans-cyclopropylamines of formula (12), (26), (32), (48), (55) and (61). Separation can also be performed at other stages of the procedure, for example upon a compound of formula (45).
  • a suitable method to obtain the enantiomers of the trans cyclopropylamines (12), (26), (32), (48), (55) and (61) comprises contacting a trans-substituted cyclopropylamine with a chiral recrystallization agent in a solvent (particularly under conditions that are sufficient for the crystallization of the salt of the chiral recrystallization agent and the trans substituted cyclopropylamine); and isolating the crystallized salt of the chiral recrystallization agent and the trans substituted cyclopropylamine, thereby preparing an enantiomer of a trans N-substituted cyclopropylamine.
  • a suitable chiral recrystallization agent is S(+) mandelic acid, D( ⁇ ) tartaric acid, L(+) tartaric acid, L( ⁇ ) di-p-toluoyl tartaric acid, or R( ⁇ ) mandelic acid.
  • Suitable solvents are tetrahydrofuran, ethanol or mixtures thereof with H 2 O.
  • the stereochemical configuration is defined by the chemical name indicated for the respective compound, even though the drawn structure may represent a more specific configuration. Nevertheless, the invention relates to all stereoisomers of the compounds described and defined herein. Accordingly, the invention encompasses the compounds described in the Examples as defined by their chemical names and, in addition thereto, also the corresponding compounds having the absolute configuration shown in the respective drawn structures.
  • ACN acetonitrile
  • AcOH acetic acid
  • aq aqueous
  • Boc tert-butyloxycarbonyl
  • (Boc) 2 O di-tert-butyl 1,2-dicarbonate
  • brm broad multiplet
  • brs broad singlet
  • Cu(acac) 2 copper(II) acetylacetonate
  • d doublet
  • DCE 1,2-dichloroethane
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • DPPA diphenylphosphoryl azide
  • Et 2 O diethyl ether
  • EtOAc ethyl acetate
  • HPLC high performance liquid chromatography
  • m multiplet
  • MEM methoxy methyl ether
  • MeOH methanol
  • NBS N-bromosuccinimide
  • NMR nuclear magnetic resonance
  • Pd 2 (dba) 3 tris
  • Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et 2 O (3 ⁇ 10 mL); the organic layers were washed with brine (2 ⁇ 15 mL), dried over anhydrous Na 2 SO 4 and filtered.
  • Triethyl phosphonoacetate (259 mL, 1.3 mol) was added slowly dropwise to a solution of Potassium-tert-butoxide (145 g, 1.29 mol) in dry THF (2 L) at ⁇ 5° C. and stirred for 30-45 mins. Then a solution of 4-(benzyloxy)benzaldehyde (Intermediate C, 230 g, 1.08 mol) in dry THF (1.5 L) was added slowly dropwise at ⁇ 10° C. over a period of 15 mins and stirred for 30 mins. After completion, the reaction mixture was poured into ice water (1 L) and extracted with EtOAc (2 ⁇ 1.5 L).
  • Trimethyl sulfoxonium iodide (224 g, 1.02 mol) was added portion wise to a suspension of NaH (40.8 g, 1.02 mol) in dry DMSO (2 L) at RT over a period of 20 min and stirred for 1 h till the formation of a clear solution.
  • a solution of (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (Intermediate D, 240 g, 0.85 mol) in dry DMSO (2 L) was added dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (2 L), extracted with EtOAc (2 ⁇ 1 L).
  • Triethyl phosphonoacetate (26.6 g, 118.8 mmol) was added slowly dropwise to a mixture of Potassium-tert-butoxide (14.5 g, 129.6 mmol) in dry THF (200 mL) at ⁇ 5° C., stirred for 20 min and then a solution of 6-bromopyridine-3-carboxaldehyde (20 g, 108 mmol) in dry THF (100 mL) was added slowly dropwise at ⁇ 5° C. and stirred for 30 min. After completion, the reaction mixture was poured into ice water (350 mL) and extracted with EtOAc (2 ⁇ 300 mL).
  • Trimethyl sulfoxonium iodide (20.8 g, 94.7 mmol) was added in small portions to a suspension of sodium hydride (4 g, 170.6 mmol) in dry DMSO (400 mL) at rt., stirred for 1 h until clear solution was obtained.
  • a solution of (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate (Intermediate 1.20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h. After completion, the reaction mixture was poured into ice water (700 mL), extracted with EtOAc (2 ⁇ 350 mL).
  • Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly in small portions over a period of 20 min. to a suspension of sodium hydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h, till the formation of clear solution. Then a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (Intermediate N, 5 g, 0.01968), in dry DMSO (20 mL) was added slowly dropwise, stirred at rt for 30 mins.
  • reaction mixture was poured into ice water (200 mL), extracted with EtOAc (2 ⁇ 150 mL). Combined organic extracts were washed with ice water (2 ⁇ 150 mL), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and evaporated to get (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (4 g, 75.9%) as a green liquid. The crude is carried to next step without further purification.
  • a solution of triethyl phosphonoacetate (66.75 mL, 336.44 mmol) was added dropwise to a solution of Potassium-tert-butoxide (37.7 g, 280.37 mmol) in dry THF (300 mL) at ⁇ 5° C. over a period of 10 mins and stirred at 0° C. for 30 mins.
  • a solution of nicotinaldehyde (30 g, 280.37 mmol) in dry THF (50 mL) was added dropwise at 0° C. over a period of 15 mins and stirred at RT for 2 h.
  • Trimethyl sulfoxonium iodide 14.90 g, 67.76 mmol was added portion wise to a suspension of NaH (2.71 g, 67.76 mmol) in dry DMSO (100 mL) at RT over a period of 20 min. and stirred for 1 h till the formation of a clear solution.
  • a solution of (E)-ethyl 3-(pyridin-3-yl)acrylate (Intermediate S, 10 g, 56.47 mmol) in dry DMSO (50 mL) was added dropwise and stirred at RT for 20 min. After completion, the reaction mixture was poured into ice water (200 mL), extracted with EtOAc (2 ⁇ 200 mL).
  • Trimethyl sulfoxonium iodide 14.40 g, 65.49 mmol was added portionwise to a suspension of NaH (2.61 g, 108.75 mmol) in dry DMSO (200 mL) at RT over a period of 20 min and stirred for 1 h till the formation of clear solution.
  • a solution of (E)-ethyl 3-(thiazol-5-yl)acrylate (Intermediate Y, 10 g, 54.57 mmol) in dry DMSO (50 mL) was then added dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (2 ⁇ 100 mL).
  • Ethyl chloroformate (3.34 g, 30.76 mmol) was added to a solution of trans-2-(thiazol-5-yl)cyclopropanecarboxylic acid (Intermediate AA, 4 g, 26.3 mmol) and triethylamine (3.62 g, 35.50 mmol) in acetone (40 mL) at ⁇ 20° C., stirred at same temperature for 1 h. A solution of NaN 3 (2.84 g, 47.33 mmol) in water (10 mL) was then added and stirred at RT for 30 mins.
  • reaction mixture was filtered under inert atmosphere and washed with hexane (10 mL), EtOAC (5 mL), and dried under reduced pressure to get (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine dihydrochloride (50 mg, 86.2%) as a pale yellow powder.
  • Triethyl phosphonoacetate (66.53 g, 296.8 mmol) was added to a solution of potassium-tert-butoxide (33.3 g, 296.8 mmol) in dry THF (500 mL) at ⁇ 5° C. and stirred for 30-45 min at the same temperature. Then, a solution of 4-((2-methoxyethoxy)methoxy)benzaldehyde (Intermediate AK, 52 g, 247 mmol) in dry THF (100 mL) was added dropwise over a period of 15 min at ⁇ 5° C. and stirred for 30 min at the same temperature.
  • Trimethyl sulfoxonium iodide (53.7 g, 244 mmol) was added portionwise over a period of 20 min to a suspension of sodium hydride (9.58 g, 399 mmol) in dry DMSO (143 mL) and stirred at RT for 1 h, until a clear solution was formed.
  • 2-fluorobenzyl bromide (5.83 mL, 48.13 mmol) was added to a solution of tert-butyl ((trans)-2-(4-hydroxyphenyl)cyclopropyl)carbamate (Intermediate AR, 10.0 g, 40.11 mmol) and K 2 CO 3 (11.07 g, 80.22 mmol) in dry DMF (100 mL) at 0° C. and stirred at RT for 18 h. After completion, the reaction mixture was poured into ice water (350 mL) and extracted with EtOAc (2 ⁇ 200 mL).
  • t-BuOK (4.2 g, 37.63 mmol) was added portionwise to a solution of methyltriphenylphosphonium bromide (12.5 g, 35.13 mmol) in dry Et 2 O (40 mL) at 0° C. and stirred at 0° C. for 30 mins. Then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) in dry Et 2 O (25 mL) was added and stirred at RT for 16 h. After completion, the reaction mixture was poured into saturated NH 4 Cl solution (25 mL) and extracted with EtOAc (2 ⁇ 50 mL).
  • Zinc powder (4.5 g, 1.5 weight equiv) was added portionwise to a solution of tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate AY, 3 g, 9.77 mmol) in saturated NH 4 Cl (1.81 g, 34.20 mmol in Methanol 30 ml) at RT and stirred for 4 h. After completion, the reaction mixture was filtered through a pad of celite and the solvent was evaporated.
  • Methanesulphonyl chloride (55.82 mL, 0.494 mmol) was added to a solution of 3-bromo-4-methoxyaniline (100 mg, 0.494 mmol) in pyridine (1 mL) at 0° C. and stirred at RT for 2 h. After completion, reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (2 ⁇ 15 mL). The combined extracts were washed with water (3 ⁇ 10 mL), brine (15 mL) and dried over anhydrous Na 2 SO 4 filtered, and evaporated.
  • reaction mixture was poured into ice water (15 mL) and extracted with EtOAc (2 ⁇ 20 mL). The combined organic extracts were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na 2 SO 4 filtered, and evaporated under reduced pressure.
  • reaction mixture was poured into ice water (15 mL) and extracted with EtOAc (2 ⁇ 20 mL). The combined extracts were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na 2 SO 4 filtered, and evaporated.
  • the crude residue was purified by column chromatography (SiO 2 ) using EtOAc:Hexane (3:7) to get tert-butyl ((trans)-2-(3′-amino-[1,1′-biphenyl]-4-yl)cyclopropyl)carbamate (100 mg, 38.6%) as a light yellow solid.
  • Example 1 describes a racemic, which was the combination of the two different conformations regarding to the cyclopropyl ring ((1R,2S and 1S,2R). The synthesis of each of these isomers was performed as follows:
  • Step 1 The following compounds can be synthesized following the methodology described for example 1 by using the corresponding intermediates.
  • Step 2 was only performed in case the intermediate used in the reductive alkylation (Step 1) contained a Boc (tert-butyloxycarbonyl) protecting group
  • Step 2 was only performed when the intermediate used in the reductive alkylation (Step 1) contained a Boc (tert-butyloxycarbonyl) protecting group.
  • Step 2 (Boc-deprotection) was performed with TFA in dichloromethane and the compound was obtained as a trifluoroacetate salt.
  • This compound was obtained as free amine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Pyrane Compounds (AREA)
US14/352,711 2011-10-20 2012-10-22 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors Active US9487512B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/352,711 US9487512B2 (en) 2011-10-20 2012-10-22 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
EP11382325 2011-10-20
EP11382325.6 2011-10-20
EP11382325 2011-10-20
EP11382331.4 2011-10-27
EP11382331 2011-10-27
EP11382331 2011-10-27
US201161558367P 2011-11-10 2011-11-10
US201161558365P 2011-11-10 2011-11-10
PCT/EP2012/070898 WO2013057320A1 (en) 2011-10-20 2012-10-22 (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors
US14/352,711 US9487512B2 (en) 2011-10-20 2012-10-22 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/070898 A-371-Of-International WO2013057320A1 (en) 2011-10-20 2012-10-22 (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/271,772 Division US9944601B2 (en) 2011-10-20 2016-09-21 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US15/271,772 Continuation US9944601B2 (en) 2011-10-20 2016-09-21 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

Publications (2)

Publication Number Publication Date
US20150025054A1 US20150025054A1 (en) 2015-01-22
US9487512B2 true US9487512B2 (en) 2016-11-08

Family

ID=48140381

Family Applications (3)

Application Number Title Priority Date Filing Date
US14/352,711 Active US9487512B2 (en) 2011-10-20 2012-10-22 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US15/271,772 Active US9944601B2 (en) 2011-10-20 2016-09-21 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US15/911,535 Active US10329256B2 (en) 2011-10-20 2018-03-05 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

Family Applications After (2)

Application Number Title Priority Date Filing Date
US15/271,772 Active US9944601B2 (en) 2011-10-20 2016-09-21 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US15/911,535 Active US10329256B2 (en) 2011-10-20 2018-03-05 (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

Country Status (12)

Country Link
US (3) US9487512B2 (enrdf_load_stackoverflow)
EP (2) EP2768805B1 (enrdf_load_stackoverflow)
JP (2) JP6215212B2 (enrdf_load_stackoverflow)
KR (1) KR102139537B1 (enrdf_load_stackoverflow)
CN (2) CN104203914B (enrdf_load_stackoverflow)
AU (2) AU2012324803B9 (enrdf_load_stackoverflow)
BR (1) BR112014009306B1 (enrdf_load_stackoverflow)
CA (1) CA2852355C (enrdf_load_stackoverflow)
IL (1) IL232102A (enrdf_load_stackoverflow)
MX (1) MX356344B (enrdf_load_stackoverflow)
RU (1) RU2681211C2 (enrdf_load_stackoverflow)
WO (1) WO2013057320A1 (enrdf_load_stackoverflow)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9944601B2 (en) 2011-10-20 2018-04-17 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10214477B2 (en) 2011-10-20 2019-02-26 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10221125B2 (en) 2015-05-06 2019-03-05 Oryzon Genomics, S.A. Solid forms
US10265279B2 (en) 2016-03-15 2019-04-23 Oryzon Genomics, S.A. Combinations of LSD1 inhibitors for use in the treatment of solid tumors
US10780081B2 (en) 2016-06-10 2020-09-22 Oryzon Genomics, S.A. Method of treating multiple sclerosis employing a LSD1-inhibitor
US11013698B2 (en) 2016-03-15 2021-05-25 Oryzon Genomics S.A. Combinations of LSD1 inhibitors for the treatment of hematological malignancies

Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010084160A1 (en) 2009-01-21 2010-07-29 Oryzon Genomics S.A. Phenylcyclopropylamine derivatives and their medical use
BR112012006572A2 (pt) 2009-09-25 2016-04-26 Oryzon Genomics Sa inibidores de demetilase-1 de lisina específicos e seu uso
WO2011042217A1 (en) 2009-10-09 2011-04-14 Oryzon Genomics S.A. Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use
WO2011106573A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae
WO2011106105A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibitors for antiviral use
BR122019020471B1 (pt) 2010-04-19 2021-06-22 Oryzon Genomics S.A. Inibidores da desmetilase específica para lisina 1, seus usos e método para sua identificação, e composições farmacêuticas
SMT201800323T1 (it) 2010-07-29 2018-07-17 Oryzon Genomics Sa Inibitori di demetilasi lsd1 a base di arilciclopropilammina e loro uso medico
WO2012013727A1 (en) 2010-07-29 2012-02-02 Oryzon Genomics S.A. Cyclopropylamine derivatives useful as lsd1 inhibitors
WO2012045883A1 (en) * 2010-10-08 2012-04-12 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
WO2012072713A2 (en) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae
EP2712315B1 (en) 2011-02-08 2021-11-24 Oryzon Genomics, S.A. Lysine demethylase inhibitors for myeloproliferative disorders
CN103857393B (zh) 2011-03-25 2016-08-17 葛兰素史密斯克莱知识产权（第2号）有限公司 环丙基胺作为lsd1抑制剂
US10323012B2 (en) * 2012-06-05 2019-06-18 Hong Kong Baptist University Miliusanes as antiviral agents
US9751885B2 (en) 2012-10-12 2017-09-05 Takeda Pharmaceutical Company Limited Cyclopropanamine compound and use thereof
EP2740474A1 (en) 2012-12-05 2014-06-11 Instituto Europeo di Oncologia S.r.l. Cyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a
WO2014194280A2 (en) * 2013-05-30 2014-12-04 The Board of Regents of the Nevada System of Higher Education on behalf of the University of Novel suicidal lsd1 inhibitors targeting sox2-expressing cancer cells
MX383590B (es) 2013-08-06 2025-03-11 Imago Biosciences Inc Inhibidores de kdm1a para el tratamiento de enfermedades.
TWI685483B (zh) 2014-02-13 2020-02-21 美商英塞特控股公司 作為ｌｓｄ１抑制劑之環丙胺
RS59534B1 (sr) 2014-02-13 2019-12-31 Incyte Corp Ciklopropilamini kao lsd1 inhibitori
EP3392244A1 (en) 2014-02-13 2018-10-24 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
US9527835B2 (en) * 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
BR112016023382B1 (pt) 2014-04-11 2023-01-10 Takeda Pharmaceutical Company Limited Composto, medicamento, e, uso de um composto
WO2016007722A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Triazolopyridines and triazolopyrazines as lsd1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
WO2016007736A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Imidazopyrazines as lsd1 inhibitors
SI3169666T1 (en) 2014-07-15 2018-08-31 Gruenenthal Gmbh SUBSTITUTED DERIVATIVES AZASPIRO (4.5) DECAN
TW201607923A (zh) 2014-07-15 2016-03-01 歌林達有限公司 被取代之氮螺環（４．５）癸烷衍生物
WO2016123387A1 (en) * 2015-01-30 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
HRP20250119T1 (hr) 2015-02-12 2025-03-28 Imago Biosciences Inc. Kdm1a inhibitor i njegova primjena u terapiji
EA201792205A1 (ru) 2015-04-03 2018-02-28 Инсайт Корпорейшн Гетероциклические соединения как ингибиторы lsd1
CN106045862B (zh) * 2015-04-10 2019-04-23 上海迪诺医药科技有限公司 环丙胺类螺(杂)环化合物、其药物组合物及应用
EP3286172B1 (en) * 2015-04-23 2019-06-12 Constellation Pharmaceuticals, Inc. Lsd1 inhibitors and uses thereof
MX2017015922A (es) 2015-06-12 2018-12-11 Oryzon Genomics Sa Biomarcadores asociados con inhibidores de lsd1 y usos de los mismos.
WO2017013061A1 (en) 2015-07-17 2017-01-26 Oryzon Genomics, S.A. Biomarkers associated with lsd1 inhibitors and uses thereof
UA126277C2 (uk) 2015-08-12 2022-09-14 Інсайт Корпорейшн Солі інгібітору lsd1
US10059668B2 (en) 2015-11-05 2018-08-28 Mirati Therapeutics, Inc. LSD1 inhibitors
SG11201805645QA (en) * 2015-12-29 2018-07-30 Mirati Therapeutics Inc Lsd1 inhibitors
SG11201805451TA (en) 2015-12-30 2018-07-30 Novartis Ag Immune effector cell therapies with enhanced efficacy
CN110267945A (zh) * 2016-03-01 2019-09-20 诺华股份有限公司 氰基取代的吲哚化合物及其作为lsd1抑制剂的用途
WO2017158136A1 (en) 2016-03-16 2017-09-21 Oryzon Genomics, S.A. Methods to determine kdm1a target engagement and chemoprobes useful therefor
CN107200706A (zh) * 2016-03-16 2017-09-26 中国科学院上海药物研究所 一类氟取代的环丙胺类化合物及其制备方法、药物组合物和用途
SG10202010414QA (en) 2016-04-22 2020-11-27 Incyte Corp Formulations of an lsd1 inhibitor
WO2018020366A1 (en) * 2016-07-26 2018-02-01 Glaxosmithkline Intellectual Property (No.2) Limited Crystalline (r)-mandelate salt of (1r,2s)-2-phenylcyclopropylamine
US11390590B2 (en) 2016-08-16 2022-07-19 Imago Biosciences, Inc. Methods and processes for the preparation of KDM1A inhibitors
EP3532459B1 (en) * 2016-10-26 2023-08-02 Constellation Pharmaceuticals, Inc. Lsd1 inhibitors and medical uses thereof
WO2018081342A1 (en) * 2016-10-26 2018-05-03 Constellation Pharmaceuticals, Inc. Lsd1 inhibitors and uses thereof
US20190256930A1 (en) 2016-11-03 2019-08-22 Oryzon Genomics, S.A. Biomarkers for determining responsiveness to lsd1 inhibitors
JP2020152641A (ja) * 2017-07-07 2020-09-24 国立研究開発法人理化学研究所 リジン特異的脱メチル化酵素１阻害活性を有する新規化合物、その製造方法及びその用途
AU2018309372B2 (en) 2017-08-03 2024-08-15 Oryzon Genomics, S.A. Methods of treating behavior alterations
WO2019068326A1 (en) 2017-10-05 2019-04-11 Université D'aix-Marseille INHIBITORS OF LSD1 FOR THE TREATMENT AND PREVENTION OF CARDIOMYOPATHIES
CN109745309B (zh) * 2017-11-03 2022-01-28 香港浸会大学 作为抗病毒剂的密瘤杀
AU2019265022B2 (en) 2018-05-11 2024-08-15 Imago Biosciences, Inc. KDM1A inhibitors for the treatment of disease
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
WO2020052649A1 (zh) * 2018-09-13 2020-03-19 南京明德新药研发有限公司 作为lsd1抑制剂的环丙胺类化合物及其应用
CN112672994B (zh) * 2018-09-13 2022-09-13 南昌弘益药业有限公司 作为lsd1抑制剂的杂螺环类化合物及其应用
JPWO2020138398A1 (ja) * 2018-12-28 2021-11-04 国立研究開発法人理化学研究所 リジン特異的脱メチル化酵素１を阻害する新規化合物、その製造方法及びその用途
CA3130638A1 (en) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Methods of treating borderline personality disorder
JP7535797B2 (ja) 2019-03-20 2024-08-19 オリソン ヘノミクス，ソシエダ アノニマ 化合物バフィデムスタット（ｖａｆｉｄｅｍｓｔａｔ）などｋｄｍ１ａ阻害剤を使用した注意欠陥多動性障害の処置方法
CN112110936B (zh) * 2019-06-20 2021-12-07 沈阳药科大学 四氢喹啉类衍生物及其制备方法和应用
WO2021004610A1 (en) 2019-07-05 2021-01-14 Oryzon Genomics, S.A. Biomarkers and methods for personalized treatment of small cell lung cancer using kdm1a inhibitors
WO2021058024A1 (zh) * 2019-09-29 2021-04-01 南京明德新药研发有限公司 Lsd1抑制剂
EP3964204A1 (en) 2020-09-08 2022-03-09 Université d'Aix-Marseille Lsd1 inhibitors for use in the treatment and prevention of fibrosis of tissues
CN112451671B (zh) * 2020-12-02 2021-11-02 武汉大学 KDM1A在抑制RNA病毒刺激下干扰素IFNβ表达中的应用
WO2022171044A1 (zh) * 2021-02-09 2022-08-18 南昌弘益药业有限公司 一种氧氮杂螺环化合物、其盐型及其晶型
CN113750095B (zh) * 2021-03-10 2023-07-04 中国医学科学院医药生物技术研究所 含有环丙基骨架的化合物在制备治疗和/或预防冠状病毒感染药物中的应用
CN113797199B (zh) * 2021-03-31 2023-05-26 中国医学科学院医药生物技术研究所 含有环丙基骨架的甲基转移酶抑制剂在治疗黄病毒属病毒感染药物中的应用
US20250073232A1 (en) 2021-04-08 2025-03-06 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
CN113200967B (zh) * 2021-05-07 2022-05-24 中国人民解放军陆军军医大学 吲哚苯醌类化合物、其制备方法及其应用
JP2023147179A (ja) * 2022-03-29 2023-10-12 大日精化工業株式会社 抗ウイルス剤、抗ウイルス性樹脂組成物、及び抗ウイルス性物品
JP2025516648A (ja) 2022-05-09 2025-05-30 オリゾン・ゲノミクス・ソシエダッド・アノニマ Ｌｓｄ１阻害薬を用いるｎｆ１変異腫瘍の治療法
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
CN120529900A (zh) 2022-11-24 2025-08-22 奥莱松基因组股份有限公司 用于治疗癌症的LSD1抑制剂和Menin抑制剂的组合
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors

Citations (131)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3106578A (en) 1960-09-16 1963-10-08 Smith Kline French Lab Nu-phenethyl-2-phenylcyclopropylamine derivatives
US3365458A (en) 1964-06-23 1968-01-23 Aldrich Chem Co Inc N-aryl-n'-cyclopropyl-ethylene diamine derivatives
US3471522A (en) 1967-09-29 1969-10-07 Aldrich Chem Co Inc N-cyclopropyl-n'-furfuryl-n'-methyl ethylene diamines
US3532712A (en) 1967-09-29 1970-10-06 Aldrich Chem Co Inc N'-cyclopropyl ethylenediamine derivatives
US3532749A (en) 1965-05-11 1970-10-06 Aldrich Chem Co Inc N'-propargyl-n**2-cyclopropyl-ethylenediamines and the salts thereof
GB1307341A (en) 1970-01-26 1973-02-21 Robins Co Inc A H 5-azaspiro-2,4-heptane-4,6-diones
US3758684A (en) 1971-09-07 1973-09-11 Burroughs Wellcome Co Treating dna virus infections with amino purine derivatives
JPS57188590A (en) 1981-05-15 1982-11-19 University Patents Inc Novel mitomycin derivative
US4409243A (en) 1981-11-09 1983-10-11 Julian Lieb Treatment of auto-immune and inflammatory diseases
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US4530901A (en) 1980-01-08 1985-07-23 Biogen N.V. Recombinant DNA molecules and their use in producing human interferon-like polypeptides
US4617389A (en) 1981-05-15 1986-10-14 University Patents, Inc. Mitomycin analogs
WO1994027947A1 (en) 1993-06-01 1994-12-08 Rhone-Poulenc Rorer Ltd. PHENYLCYCLOPROPANE COMPOUNDS AND THEIR USE AS cAMP AND TNF INHIBITORS
WO1996038141A1 (en) 1995-05-30 1996-12-05 Gliatech, Inc. 2-(1h-4(5)-imidazoyl) cyclopropyl derivatives
WO1998018459A1 (en) 1996-10-31 1998-05-07 University Of Iowa Research Foundation Use of phenylcyclopropylamines to stimulate tear secretion
WO1999005143A1 (en) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO1999005142A1 (en) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO1999031072A1 (en) 1997-12-18 1999-06-24 E.I. Du Pont De Nemours And Company Cyclohexylamine arthropodicides and fungicides
WO1999054440A1 (en) 1998-04-21 1999-10-28 Micromet Gesellschaft Für Biomedizinische Forschung Mbh CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF
WO1999067203A1 (en) 1998-06-22 1999-12-29 Astrazeneca Ab Novel compounds useful in pain management
US6043393A (en) 1996-11-18 2000-03-28 Bayer Aktiengesellschaft Method for preparing cyclopropylamines
WO2000034283A1 (en) 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
WO2001092264A1 (en) 2000-05-26 2001-12-06 Schering Corporation Adenosine a2a receptor antagonists
JP2001354563A (ja) 2000-06-09 2001-12-25 Sankyo Co Ltd 置換ベンジルアミン類を含有する医薬
US6337074B1 (en) 1996-07-26 2002-01-08 Medical Research Council Anti-herpesviral agent
EP1193268A1 (en) 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases
WO2002079152A1 (en) 2001-03-29 2002-10-10 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US20030008844A1 (en) 2001-05-17 2003-01-09 Keryx Biopharmaceuticals, Inc. Use of sulodexide for the treatment of inflammatory bowel disease
WO2003087064A1 (en) 2002-04-18 2003-10-23 Ucb, S.A. Chemical compounds with dual activity, processes for their preparation and pharmaceutical compositions
WO2003093297A2 (en) 2002-05-03 2003-11-13 Exelixis, Inc. Protein kinase modulators and methods of use
WO2003096989A2 (en) 2002-05-17 2003-11-27 Department Of Health And Human Services Anti tubercular drug: compositions and methods
US20030236225A1 (en) 2002-05-17 2003-12-25 Protopopova Marina Nikolaevna Methods of use and compositions for the diagnosis and treatment of infectious disease
US20040048802A1 (en) 2002-05-20 2004-03-11 Amy Ripka Hepatitis C virus inhibitors
WO2004020415A1 (en) 2002-08-27 2004-03-11 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase mmp12.
US20040058282A1 (en) 2002-09-10 2004-03-25 Fuji Photo Film Co., Ltd. Method of processing silver halide photosensitive material
JP2004126566A (ja) 2002-09-10 2004-04-22 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料の処理方法
WO2004055010A2 (en) 2002-12-13 2004-07-01 Smithkline Beecham Corporation Cyclopropyl compounds as ccr5 antagonists
US20040132820A1 (en) 1996-02-15 2004-07-08 Jean Gosselin Agents with leukotriene B4-like antiviral (DNA) and anti-neoplastic activities
WO2004062601A2 (en) 2003-01-08 2004-07-29 Chiron Corporation Antibacterial agents
US20040147741A1 (en) 2001-05-09 2004-07-29 Gruenenthal Gmbh Substituted 2-pyridine cyclohexane-1,4-diamine compounds
WO2004065367A1 (en) 2003-01-22 2004-08-05 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2004072086A2 (en) 2003-02-14 2004-08-26 Pfizer Limited Antiparasitic terpene alkaloids
US20040176469A1 (en) 2000-07-27 2004-09-09 Thomas Nadackal Thomas Compositions and methods to prevent toxicity of antiinflammatory agents and enhance their efficacy
US6809120B1 (en) 1998-01-13 2004-10-26 University Of Saskatchewan Technologies Inc. Composition containing propargylamine for enhancing cancer therapy
US20040254158A1 (en) 2002-05-10 2004-12-16 Qiao Jennifer X. 1,1-Disubstituted cycloalkyl derivatives as factor Xa inhibitors
US20050009832A1 (en) 2003-02-20 2005-01-13 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
WO2005009941A1 (en) 2003-07-03 2005-02-03 Eli Lilly And Company Indane derivates as muscarinic receptor agonists
WO2005023761A2 (en) 2003-09-11 2005-03-17 Kemia, Inc. Cytokine inhibitors
WO2005025558A1 (en) 2003-09-12 2005-03-24 Applied Reserach Systems Ars Holding N.V. Sulfonamide derivatives for the treatment of diabetes
WO2005037843A1 (en) 2003-10-14 2005-04-28 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
WO2005058884A2 (en) 2003-12-15 2005-06-30 Japan Tobacco Inc. Cyclopropane compounds and pharmaceutical use thereof
WO2005058808A1 (en) 2003-12-15 2005-06-30 Japan Tobacco Inc. N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof
WO2005058883A1 (en) 2003-12-15 2005-06-30 Almirall Prodesfarma Ag 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists
US20050154056A1 (en) 2003-11-07 2005-07-14 Pharmacia & Upjohn Company Inhibitors of HCV NS5B polymerase
WO2005103003A2 (en) 2004-04-26 2005-11-03 Pfizer Inc. Pyrrolopyridine derivatives and their use as hiv-integrase inhibitors
US20060116370A1 (en) 2004-11-29 2006-06-01 Boehringer Ingelheim International Gmbh Substituted pteridines for the treatment of inflammatory diseases
US20060148904A1 (en) 2002-05-17 2006-07-06 Protopopova Marina N Anti tubercular drug: compositions and methods
WO2006071608A2 (en) 2004-12-16 2006-07-06 President And Fellows Of Harvard College Histone demethylation mediated by the nuclear amine oxidase homolog lsd1
WO2006087206A2 (en) 2005-02-18 2006-08-24 Universitätsklinikum Freiburg Androgen receptor-dependent gene expression control by inhibiting the amine oxidase activity of lysine-specific demethylase (lsd1)
US20060211709A1 (en) 2002-05-03 2006-09-21 Buhr Chris A Protein kinase modulators and methods of use
US20060270673A1 (en) 2003-04-24 2006-11-30 Merck & Co., Inc. Inhibitors of akt activity
US20060275366A1 (en) 2005-06-02 2006-12-07 Schering Corporation Controlled-release formulation
US20060287287A1 (en) 2005-06-21 2006-12-21 Samuel Gerritz Aminoacetamide acyl guanidines as beta-secretase inhibitors
WO2007000248A1 (en) 2005-06-28 2007-01-04 Sanofi-Aventis Heteroaryl-substituted amides comprising an unsaturated or cyclic linker group, and their use as pharmaceuticals
WO2007015824A2 (en) 2005-07-25 2007-02-08 Intermune, Inc. Novel macrocyclic inhibitors of hepatitis c virus replication
WO2007021839A2 (en) 2005-08-10 2007-02-22 Johns Hopkins University Polyamines useful as anti-parasitic and anti-cancer therapeutics and as lysine-specific demethylase inhibitors
WO2007025144A1 (en) 2005-08-24 2007-03-01 University Of Illinois - Chicago 5-ht2c receptor agonists as anorectic agents
WO2007025709A2 (en) 2005-08-31 2007-03-08 Novartis Ag Organic compounds
WO2007035873A1 (en) 2005-09-21 2007-03-29 Pharmacopeia, Inc. Purinone derivatives for treating neurodegenerative diseases
US20070213338A1 (en) 2003-10-21 2007-09-13 Lebsack Alec D Triazolo-Pyridazine Compounds and Derivatives Thereof Useful in the Treatment of Neuropathic Pain
WO2007106016A1 (en) 2006-03-14 2007-09-20 Astrazeneca Ab Bezothiazol derivatives as beta2 adrenoreceptor agonists
WO2007134799A1 (en) 2006-05-18 2007-11-29 Syngenta Participations Ag Novel microbiocides
WO2008033466A2 (en) 2006-09-14 2008-03-20 Combinatorx (Singapore) Pre. Ltd. Compositions and methods for treatment of viral diseases
US7399825B2 (en) 2003-12-24 2008-07-15 Lipps Binie V Synthetic peptide, inhibitor to DNA viruses
WO2008116156A2 (en) 2007-03-21 2008-09-25 The Regents Of The University Of Michigan Methods and compositions for treating diseases and conditions associated with mitochondrial function
WO2008127734A2 (en) 2007-04-13 2008-10-23 The Johns Hopkins University Lysine-specific demethylase inhibitors
US20080269228A1 (en) 2007-04-26 2008-10-30 Moore Joel D Hydrazide-containing hepatitis c serine protease inhibitors
WO2009001132A1 (en) 2007-06-27 2008-12-31 Astrazeneca Ab Pyrazinone derivatives and their use in the treatment of lung diseases
WO2009023179A2 (en) 2007-08-10 2009-02-19 Genelabs Technologies, Inc. Nitrogen containing bicyclic chemical entities for treating viral infections
WO2009039134A1 (en) 2007-09-17 2009-03-26 Abbott Laboratories Anti-infective pyrimidines and uses thereof
WO2009052078A1 (en) 2007-10-19 2009-04-23 Boehringer Ingelheim International Gmbh Ccr10 antagonists
WO2009097278A1 (en) 2008-01-28 2009-08-06 Janssen Pharmaceutica N.V. 6-SUBSTITUTED-THIO-2-AMINO-QUINOLINE DERIVATIVES USEFUL AS INHIBITORS OF β-SECRETASE (BACE)
WO2009109991A2 (en) 2008-01-23 2009-09-11 Sun Pharma Advanced Research Company Ltd., Novel hydrazide containing tyrosine kinase inhibitors
WO2009117515A2 (en) 2008-03-19 2009-09-24 Aurimmed Pharma, Inc. Novel compounds advantageous in the treatment of central nervous system diseases and disorders
US20090247530A1 (en) 2008-03-27 2009-10-01 Grunenthal Gmbh Substituted 4-aminocyclohexane derivatives
US7611704B2 (en) 2002-07-15 2009-11-03 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections using antibodies and immunoconjugates to aminophospholipids
WO2009145856A1 (en) 2008-04-16 2009-12-03 Portola Pharmaceuticals, Inc. 2, 6-diamino-pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors
US7628993B2 (en) 2006-07-20 2009-12-08 Vical Incorporated Compositions and methods for vaccinating against HSV-2
WO2009153197A1 (en) 2008-06-18 2009-12-23 F. Hoffmann-La Roche Ag Halo-substituted pyrimidodiazepines as plkl inhibitors
US20100016262A1 (en) 2007-10-18 2010-01-21 Yale University Compositions and methods for reducing hepatotoxicity associated with drug administration and treating non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and associated cirrhosis
WO2010011845A2 (en) 2008-07-24 2010-01-28 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Methods of preventing or treating viral infection or reactivation after latency in a host using inhibitors of the lsd1 protein
WO2010014921A2 (en) 2008-08-01 2010-02-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor antagonists and partial agonists
WO2010030592A1 (en) 2008-09-11 2010-03-18 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis c
WO2010043721A1 (en) 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use
WO2010084160A1 (en) 2009-01-21 2010-07-29 Oryzon Genomics S.A. Phenylcyclopropylamine derivatives and their medical use
WO2010085749A2 (en) 2009-01-23 2010-07-29 Northwestern University Potent and selective neuronal nitric oxide synthase inhibitors with improved membrane permeability
WO2010099527A1 (en) 2009-02-27 2010-09-02 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US7799782B2 (en) 2003-03-03 2010-09-21 Array Biopharma Inc. P38 inhibitors and methods of use thereof
US20100240649A1 (en) 2006-07-05 2010-09-23 Hesheng Zhang Quinazoline and quinoline derivatives as irreversible protein tyrosine kinase inhibitors
EP2233495A1 (en) 2007-12-26 2010-09-29 Shionogi & Co., Ltd. Glycosylated glycopeptide antibiotic derivative
US20100292225A1 (en) 2009-05-15 2010-11-18 Sylvie Chamoin Aryl pyridine as aldosterone synthase inhibitors
WO2010139784A1 (en) 2009-06-05 2010-12-09 Universitätsklinikum Freiburg Lysine-specific demethylase 1 (lsd1) is a biomarker for breast cancer
WO2010143582A1 (ja) 2009-06-11 2010-12-16 公立大学法人名古屋市立大学 フェニルシクロプロピルアミン誘導体及びlsd1阻害剤
US20100324147A1 (en) 2009-06-02 2010-12-23 Mccafferty Dewey G Arylcyclopropylamines and methods of use
WO2011022489A2 (en) 2009-08-18 2011-02-24 The Johns Hopkins University (bis) urea and (bis) thiourea compounds as epigenic modulators of lysine-specific demethylase 1 and methods of treating disorders
WO2011031934A1 (en) 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
WO2011035941A1 (en) 2009-09-25 2011-03-31 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
WO2011042217A1 (en) 2009-10-09 2011-04-14 Oryzon Genomics S.A. Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use
WO2011057262A2 (en) 2009-11-09 2011-05-12 Evolva Inc. Treatment of infections with tp receptor antagonists
WO2011106105A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibitors for antiviral use
WO2011132083A2 (en) 2010-04-20 2011-10-27 Actavis Group Ptc Ehf Novel process for preparing phenylcyclopropylamine derivatives using novel intermediates
WO2011131697A1 (en) 2010-04-19 2011-10-27 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
WO2011131576A1 (en) 2010-04-20 2011-10-27 Università Degli Studi Di Roma "La Sapienza" Tranylcypromine derivatives as inhibitors of histone demethylase lsd1 and/or lsd2
WO2012001531A2 (en) 2010-06-30 2012-01-05 Actavis Group Ptc Ehf Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor
WO2011106106A3 (en) 2010-02-24 2012-01-19 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae
WO2011113005A3 (en) 2010-03-12 2012-01-19 The Johns Hopkins University Compositions and methods for combinations of oligoamines with 2-difluoromethylornithine (dfmo)
WO2012013727A1 (en) 2010-07-29 2012-02-02 Oryzon Genomics S.A. Cyclopropylamine derivatives useful as lsd1 inhibitors
WO2012013726A1 (en) 2010-07-30 2012-02-02 Schrader Electronics Limited Tire pressure monitoring system with wheel position allocation through correlating with wheel rotation speed
WO2012034116A2 (en) 2010-09-10 2012-03-15 The Johns Hopkins University Small molecules as epigenetic modulators of lysine-specific demethylase 1 and methods of treating disorders
WO2012042042A1 (en) 2010-09-30 2012-04-05 Oryzon Genomics S.A. Selective lsd1 and dual lsd1/mao-b inhibitors for modulating diseases associated with alterations in protein conformation
WO2012045883A1 (en) 2010-10-08 2012-04-12 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
WO2012072713A2 (en) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae
WO2012107499A1 (en) 2011-02-08 2012-08-16 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders
WO2012107498A1 (en) 2011-02-08 2012-08-16 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative disorders
WO2012135113A2 (en) 2011-03-25 2012-10-04 Glaxosmithkline Llc Cyclopropylamines as lsd1 inhibitors
WO2012156531A2 (en) 2011-05-19 2012-11-22 Oryzon Genomics, S.A. Lysine demethylase inhibitors for inflammatory diseases or conditions
WO2013022047A1 (ja) * 2011-08-09 2013-02-14 武田薬品工業株式会社 シクロプロパンアミン化合物
WO2012156537A9 (en) 2011-05-19 2013-03-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors such as cyclylcylopropamine derivatives for use in the treatment of thrombosis and cardiovascular diseases
WO2013057322A1 (en) 2011-10-20 2013-04-25 Oryzon Genomics, S.A. (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors
WO2013057320A1 (en) 2011-10-20 2013-04-25 Oryzon Genomics, S.A. (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
GB913385A (en) 1960-09-01 1962-12-19 Ici Ltd Esters of diboronic acids
JPS59357B2 (ja) 1981-02-20 1984-01-06 富士通株式会社 洗滌用グロ−ブボツクス天井の防滴構造
JP2001354363A (ja) 2000-06-13 2001-12-25 Kanebo Ltd 結束帯が取り付けられた電気機器
DE202004021379U1 (de) * 2003-02-12 2008-02-21 Ciba Specialty Chemicals Holding Inc. Kristalline Formen von Pitivastatin Calcium
US8130552B2 (en) 2008-09-11 2012-03-06 Sandisk Technologies Inc. Multi-pass programming for memory with reduced data storage requirement
TW201119676A (en) 2009-10-15 2011-06-16 Abbott Lab Dual variable domain immunoglobulins and uses thereof
SMT201800323T1 (it) * 2010-07-29 2018-07-17 Oryzon Genomics Sa Inibitori di demetilasi lsd1 a base di arilciclopropilammina e loro uso medico
EP3090998A1 (en) 2015-05-06 2016-11-09 F. Hoffmann-La Roche AG Solid forms
MX2017015922A (es) 2015-06-12 2018-12-11 Oryzon Genomics Sa Biomarcadores asociados con inhibidores de lsd1 y usos de los mismos.
WO2017013061A1 (en) 2015-07-17 2017-01-26 Oryzon Genomics, S.A. Biomarkers associated with lsd1 inhibitors and uses thereof
WO2017060319A1 (en) 2015-10-09 2017-04-13 F. Hoffmann-La Roche Ag Gene expression biomarkers for personalized cancer care to epigenetic modifying agents
AU2017233898B2 (en) 2016-03-15 2022-12-15 Oryzon Genomics, S.A. Combinations of LSD1 inhibitors for use in the treatment of solid tumors
KR102511028B1 (ko) 2016-03-15 2023-03-16 오리존 지노믹스 에스.에이. 혈액 악성 종양의 치료를 위한 lsd1 억제제의 조합물
WO2017158136A1 (en) 2016-03-16 2017-09-21 Oryzon Genomics, S.A. Methods to determine kdm1a target engagement and chemoprobes useful therefor
US20190256930A1 (en) 2016-11-03 2019-08-22 Oryzon Genomics, S.A. Biomarkers for determining responsiveness to lsd1 inhibitors
WO2018083138A1 (en) 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Pharmacodynamic biomarkers for personalized cancer care using epigenetic modifying agents

Patent Citations (148)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3106578A (en) 1960-09-16 1963-10-08 Smith Kline French Lab Nu-phenethyl-2-phenylcyclopropylamine derivatives
US3365458A (en) 1964-06-23 1968-01-23 Aldrich Chem Co Inc N-aryl-n'-cyclopropyl-ethylene diamine derivatives
US3532749A (en) 1965-05-11 1970-10-06 Aldrich Chem Co Inc N'-propargyl-n**2-cyclopropyl-ethylenediamines and the salts thereof
US3471522A (en) 1967-09-29 1969-10-07 Aldrich Chem Co Inc N-cyclopropyl-n'-furfuryl-n'-methyl ethylene diamines
US3532712A (en) 1967-09-29 1970-10-06 Aldrich Chem Co Inc N'-cyclopropyl ethylenediamine derivatives
GB1307341A (en) 1970-01-26 1973-02-21 Robins Co Inc A H 5-azaspiro-2,4-heptane-4,6-diones
US3758684A (en) 1971-09-07 1973-09-11 Burroughs Wellcome Co Treating dna virus infections with amino purine derivatives
US4530901A (en) 1980-01-08 1985-07-23 Biogen N.V. Recombinant DNA molecules and their use in producing human interferon-like polypeptides
JPS57188590A (en) 1981-05-15 1982-11-19 University Patents Inc Novel mitomycin derivative
US4617389A (en) 1981-05-15 1986-10-14 University Patents, Inc. Mitomycin analogs
US4409243A (en) 1981-11-09 1983-10-11 Julian Lieb Treatment of auto-immune and inflammatory diseases
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
WO1994027947A1 (en) 1993-06-01 1994-12-08 Rhone-Poulenc Rorer Ltd. PHENYLCYCLOPROPANE COMPOUNDS AND THEIR USE AS cAMP AND TNF INHIBITORS
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
WO1996038141A1 (en) 1995-05-30 1996-12-05 Gliatech, Inc. 2-(1h-4(5)-imidazoyl) cyclopropyl derivatives
US20040132820A1 (en) 1996-02-15 2004-07-08 Jean Gosselin Agents with leukotriene B4-like antiviral (DNA) and anti-neoplastic activities
US6337074B1 (en) 1996-07-26 2002-01-08 Medical Research Council Anti-herpesviral agent
WO1998018459A1 (en) 1996-10-31 1998-05-07 University Of Iowa Research Foundation Use of phenylcyclopropylamines to stimulate tear secretion
US6043393A (en) 1996-11-18 2000-03-28 Bayer Aktiengesellschaft Method for preparing cyclopropylamines
WO1999005143A1 (en) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO1999005142A1 (en) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO1999031072A1 (en) 1997-12-18 1999-06-24 E.I. Du Pont De Nemours And Company Cyclohexylamine arthropodicides and fungicides
US6809120B1 (en) 1998-01-13 2004-10-26 University Of Saskatchewan Technologies Inc. Composition containing propargylamine for enhancing cancer therapy
WO1999054440A1 (en) 1998-04-21 1999-10-28 Micromet Gesellschaft Für Biomedizinische Forschung Mbh CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF
WO1999067203A1 (en) 1998-06-22 1999-12-29 Astrazeneca Ab Novel compounds useful in pain management
WO2000034283A1 (en) 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
WO2001092264A1 (en) 2000-05-26 2001-12-06 Schering Corporation Adenosine a2a receptor antagonists
JP2001354563A (ja) 2000-06-09 2001-12-25 Sankyo Co Ltd 置換ベンジルアミン類を含有する医薬
US20040176469A1 (en) 2000-07-27 2004-09-09 Thomas Nadackal Thomas Compositions and methods to prevent toxicity of antiinflammatory agents and enhance their efficacy
EP1193268A1 (en) 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases
WO2002079152A1 (en) 2001-03-29 2002-10-10 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US20040147741A1 (en) 2001-05-09 2004-07-29 Gruenenthal Gmbh Substituted 2-pyridine cyclohexane-1,4-diamine compounds
US20040229872A1 (en) 2001-05-09 2004-11-18 Gruenenthal Gmbh Substituted cyclohexane-1,4-diamine compounds with anti-diarrhea and peripheral analgesic activity
US20040162287A1 (en) 2001-05-09 2004-08-19 Gruenenthal Gmbh Substituted cyclohexane-1,4-diamine compounds
US20030008844A1 (en) 2001-05-17 2003-01-09 Keryx Biopharmaceuticals, Inc. Use of sulodexide for the treatment of inflammatory bowel disease
WO2003087064A1 (en) 2002-04-18 2003-10-23 Ucb, S.A. Chemical compounds with dual activity, processes for their preparation and pharmaceutical compositions
US20060211709A1 (en) 2002-05-03 2006-09-21 Buhr Chris A Protein kinase modulators and methods of use
WO2003093297A2 (en) 2002-05-03 2003-11-13 Exelixis, Inc. Protein kinase modulators and methods of use
US20040254158A1 (en) 2002-05-10 2004-12-16 Qiao Jennifer X. 1,1-Disubstituted cycloalkyl derivatives as factor Xa inhibitors
US20060148904A1 (en) 2002-05-17 2006-07-06 Protopopova Marina N Anti tubercular drug: compositions and methods
US20040033986A1 (en) 2002-05-17 2004-02-19 Protopopova Marina Nikolaevna Anti tubercular drug: compositions and methods
US20040019117A1 (en) 2002-05-17 2004-01-29 Protopopova Marina Nikolaevna Anti tubercular drug: compostions and methods
US20030236225A1 (en) 2002-05-17 2003-12-25 Protopopova Marina Nikolaevna Methods of use and compositions for the diagnosis and treatment of infectious disease
WO2003096989A2 (en) 2002-05-17 2003-11-27 Department Of Health And Human Services Anti tubercular drug: compositions and methods
US20040048802A1 (en) 2002-05-20 2004-03-11 Amy Ripka Hepatitis C virus inhibitors
US7611704B2 (en) 2002-07-15 2009-11-03 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections using antibodies and immunoconjugates to aminophospholipids
WO2004020415A1 (en) 2002-08-27 2004-03-11 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase mmp12.
JP2004126566A (ja) 2002-09-10 2004-04-22 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料の処理方法
US20040058282A1 (en) 2002-09-10 2004-03-25 Fuji Photo Film Co., Ltd. Method of processing silver halide photosensitive material
WO2004055010A2 (en) 2002-12-13 2004-07-01 Smithkline Beecham Corporation Cyclopropyl compounds as ccr5 antagonists
WO2004062601A2 (en) 2003-01-08 2004-07-29 Chiron Corporation Antibacterial agents
WO2004065367A1 (en) 2003-01-22 2004-08-05 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2004072086A2 (en) 2003-02-14 2004-08-26 Pfizer Limited Antiparasitic terpene alkaloids
US20050009832A1 (en) 2003-02-20 2005-01-13 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
US7799782B2 (en) 2003-03-03 2010-09-21 Array Biopharma Inc. P38 inhibitors and methods of use thereof
US20060270673A1 (en) 2003-04-24 2006-11-30 Merck & Co., Inc. Inhibitors of akt activity
WO2005009941A1 (en) 2003-07-03 2005-02-03 Eli Lilly And Company Indane derivates as muscarinic receptor agonists
WO2005023761A2 (en) 2003-09-11 2005-03-17 Kemia, Inc. Cytokine inhibitors
WO2005025558A1 (en) 2003-09-12 2005-03-24 Applied Reserach Systems Ars Holding N.V. Sulfonamide derivatives for the treatment of diabetes
WO2005037843A1 (en) 2003-10-14 2005-04-28 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
US20070213338A1 (en) 2003-10-21 2007-09-13 Lebsack Alec D Triazolo-Pyridazine Compounds and Derivatives Thereof Useful in the Treatment of Neuropathic Pain
US20050154056A1 (en) 2003-11-07 2005-07-14 Pharmacia & Upjohn Company Inhibitors of HCV NS5B polymerase
WO2005058883A1 (en) 2003-12-15 2005-06-30 Almirall Prodesfarma Ag 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists
WO2005058808A1 (en) 2003-12-15 2005-06-30 Japan Tobacco Inc. N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof
WO2005058884A2 (en) 2003-12-15 2005-06-30 Japan Tobacco Inc. Cyclopropane compounds and pharmaceutical use thereof
US7399825B2 (en) 2003-12-24 2008-07-15 Lipps Binie V Synthetic peptide, inhibitor to DNA viruses
WO2005103003A2 (en) 2004-04-26 2005-11-03 Pfizer Inc. Pyrrolopyridine derivatives and their use as hiv-integrase inhibitors
US20060116370A1 (en) 2004-11-29 2006-06-01 Boehringer Ingelheim International Gmbh Substituted pteridines for the treatment of inflammatory diseases
WO2006071608A2 (en) 2004-12-16 2006-07-06 President And Fellows Of Harvard College Histone demethylation mediated by the nuclear amine oxidase homolog lsd1
US20080139665A1 (en) 2005-02-18 2008-06-12 Roland Schuele Androgen Receptor-Dependent Gene Expression Control
EP1704859A1 (en) 2005-02-18 2006-09-27 Universitätsklinikum Freiburg Androgen receptor-dependent gene expression control by inhibiting the amine oxidase activity of lysine-specific demethylase (LSD1)
WO2006087206A2 (en) 2005-02-18 2006-08-24 Universitätsklinikum Freiburg Androgen receptor-dependent gene expression control by inhibiting the amine oxidase activity of lysine-specific demethylase (lsd1)
US20060275366A1 (en) 2005-06-02 2006-12-07 Schering Corporation Controlled-release formulation
US20060287287A1 (en) 2005-06-21 2006-12-21 Samuel Gerritz Aminoacetamide acyl guanidines as beta-secretase inhibitors
WO2007000248A1 (en) 2005-06-28 2007-01-04 Sanofi-Aventis Heteroaryl-substituted amides comprising an unsaturated or cyclic linker group, and their use as pharmaceuticals
EP1741708A1 (en) 2005-06-28 2007-01-10 Sanofi-Aventis Deutschland GmbH Heteroaryl-substituted amides comprising an unsaturated or cyclic linker group, and their use as pharmaceuticals
WO2007005896A2 (en) 2005-07-01 2007-01-11 Sequella, Inc. Anti-tubercular drugs: compositions and methods
WO2007015824A2 (en) 2005-07-25 2007-02-08 Intermune, Inc. Novel macrocyclic inhibitors of hepatitis c virus replication
WO2007021839A2 (en) 2005-08-10 2007-02-22 Johns Hopkins University Polyamines useful as anti-parasitic and anti-cancer therapeutics and as lysine-specific demethylase inhibitors
WO2007025144A1 (en) 2005-08-24 2007-03-01 University Of Illinois - Chicago 5-ht2c receptor agonists as anorectic agents
US20090203750A1 (en) 2005-08-24 2009-08-13 Alan Kozikowski 5-HT2C Receptor Agonists as Anorectic Agents
US20080242698A1 (en) 2005-08-31 2008-10-02 Peter Josef Flor Organic Compounds
WO2007025709A2 (en) 2005-08-31 2007-03-08 Novartis Ag Organic compounds
WO2007035873A1 (en) 2005-09-21 2007-03-29 Pharmacopeia, Inc. Purinone derivatives for treating neurodegenerative diseases
WO2007106016A1 (en) 2006-03-14 2007-09-20 Astrazeneca Ab Bezothiazol derivatives as beta2 adrenoreceptor agonists
WO2007134799A1 (en) 2006-05-18 2007-11-29 Syngenta Participations Ag Novel microbiocides
US20100240649A1 (en) 2006-07-05 2010-09-23 Hesheng Zhang Quinazoline and quinoline derivatives as irreversible protein tyrosine kinase inhibitors
US7628993B2 (en) 2006-07-20 2009-12-08 Vical Incorporated Compositions and methods for vaccinating against HSV-2
WO2008033466A2 (en) 2006-09-14 2008-03-20 Combinatorx (Singapore) Pre. Ltd. Compositions and methods for treatment of viral diseases
WO2008116156A2 (en) 2007-03-21 2008-09-25 The Regents Of The University Of Michigan Methods and compositions for treating diseases and conditions associated with mitochondrial function
WO2008127734A2 (en) 2007-04-13 2008-10-23 The Johns Hopkins University Lysine-specific demethylase inhibitors
US20080269228A1 (en) 2007-04-26 2008-10-30 Moore Joel D Hydrazide-containing hepatitis c serine protease inhibitors
WO2009001132A1 (en) 2007-06-27 2008-12-31 Astrazeneca Ab Pyrazinone derivatives and their use in the treatment of lung diseases
WO2009023179A2 (en) 2007-08-10 2009-02-19 Genelabs Technologies, Inc. Nitrogen containing bicyclic chemical entities for treating viral infections
WO2009039134A1 (en) 2007-09-17 2009-03-26 Abbott Laboratories Anti-infective pyrimidines and uses thereof
US20100016262A1 (en) 2007-10-18 2010-01-21 Yale University Compositions and methods for reducing hepatotoxicity associated with drug administration and treating non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and associated cirrhosis
WO2009052078A1 (en) 2007-10-19 2009-04-23 Boehringer Ingelheim International Gmbh Ccr10 antagonists
EP2233495A1 (en) 2007-12-26 2010-09-29 Shionogi & Co., Ltd. Glycosylated glycopeptide antibiotic derivative
WO2009109991A2 (en) 2008-01-23 2009-09-11 Sun Pharma Advanced Research Company Ltd., Novel hydrazide containing tyrosine kinase inhibitors
WO2009097278A1 (en) 2008-01-28 2009-08-06 Janssen Pharmaceutica N.V. 6-SUBSTITUTED-THIO-2-AMINO-QUINOLINE DERIVATIVES USEFUL AS INHIBITORS OF β-SECRETASE (BACE)
WO2009117515A2 (en) 2008-03-19 2009-09-24 Aurimmed Pharma, Inc. Novel compounds advantageous in the treatment of central nervous system diseases and disorders
US20130197095A1 (en) 2008-03-27 2013-08-01 Grünenthal GmbH Substituted 4-aminocyclohexane derivatives
US20120202810A1 (en) 2008-03-27 2012-08-09 Grunenthal Gmbh Substituted 4-aminocyclohexane derivatives
US20090247530A1 (en) 2008-03-27 2009-10-01 Grunenthal Gmbh Substituted 4-aminocyclohexane derivatives
WO2009145856A1 (en) 2008-04-16 2009-12-03 Portola Pharmaceuticals, Inc. 2, 6-diamino-pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors
WO2009153197A1 (en) 2008-06-18 2009-12-23 F. Hoffmann-La Roche Ag Halo-substituted pyrimidodiazepines as plkl inhibitors
WO2010011845A2 (en) 2008-07-24 2010-01-28 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Methods of preventing or treating viral infection or reactivation after latency in a host using inhibitors of the lsd1 protein
WO2010014921A2 (en) 2008-08-01 2010-02-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor antagonists and partial agonists
WO2010030592A1 (en) 2008-09-11 2010-03-18 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis c
WO2010043721A1 (en) 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use
US8524717B2 (en) 2008-10-17 2013-09-03 Oryzon Genomics, S.A. Oxidase inhibitors and their use
WO2010084160A1 (en) 2009-01-21 2010-07-29 Oryzon Genomics S.A. Phenylcyclopropylamine derivatives and their medical use
WO2010085749A2 (en) 2009-01-23 2010-07-29 Northwestern University Potent and selective neuronal nitric oxide synthase inhibitors with improved membrane permeability
WO2010099527A1 (en) 2009-02-27 2010-09-02 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US20100292225A1 (en) 2009-05-15 2010-11-18 Sylvie Chamoin Aryl pyridine as aldosterone synthase inhibitors
US20100324147A1 (en) 2009-06-02 2010-12-23 Mccafferty Dewey G Arylcyclopropylamines and methods of use
WO2010139784A1 (en) 2009-06-05 2010-12-09 Universitätsklinikum Freiburg Lysine-specific demethylase 1 (lsd1) is a biomarker for breast cancer
WO2010143582A1 (ja) 2009-06-11 2010-12-16 公立大学法人名古屋市立大学 フェニルシクロプロピルアミン誘導体及びlsd1阻害剤
WO2011022489A2 (en) 2009-08-18 2011-02-24 The Johns Hopkins University (bis) urea and (bis) thiourea compounds as epigenic modulators of lysine-specific demethylase 1 and methods of treating disorders
WO2011031934A1 (en) 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
WO2011035941A1 (en) 2009-09-25 2011-03-31 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
WO2011042217A1 (en) 2009-10-09 2011-04-14 Oryzon Genomics S.A. Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use
WO2011057262A2 (en) 2009-11-09 2011-05-12 Evolva Inc. Treatment of infections with tp receptor antagonists
WO2011106105A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibitors for antiviral use
WO2011106106A3 (en) 2010-02-24 2012-01-19 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae
WO2011113005A3 (en) 2010-03-12 2012-01-19 The Johns Hopkins University Compositions and methods for combinations of oligoamines with 2-difluoromethylornithine (dfmo)
WO2011131697A1 (en) 2010-04-19 2011-10-27 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
US8722743B2 (en) * 2010-04-19 2014-05-13 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
WO2011131576A1 (en) 2010-04-20 2011-10-27 Università Degli Studi Di Roma "La Sapienza" Tranylcypromine derivatives as inhibitors of histone demethylase lsd1 and/or lsd2
WO2011132083A2 (en) 2010-04-20 2011-10-27 Actavis Group Ptc Ehf Novel process for preparing phenylcyclopropylamine derivatives using novel intermediates
WO2012001531A2 (en) 2010-06-30 2012-01-05 Actavis Group Ptc Ehf Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor
WO2012013727A1 (en) 2010-07-29 2012-02-02 Oryzon Genomics S.A. Cyclopropylamine derivatives useful as lsd1 inhibitors
WO2012013726A1 (en) 2010-07-30 2012-02-02 Schrader Electronics Limited Tire pressure monitoring system with wheel position allocation through correlating with wheel rotation speed
WO2012034116A2 (en) 2010-09-10 2012-03-15 The Johns Hopkins University Small molecules as epigenetic modulators of lysine-specific demethylase 1 and methods of treating disorders
WO2012042042A1 (en) 2010-09-30 2012-04-05 Oryzon Genomics S.A. Selective lsd1 and dual lsd1/mao-b inhibitors for modulating diseases associated with alterations in protein conformation
WO2012045883A1 (en) 2010-10-08 2012-04-12 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
WO2012072713A2 (en) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae
WO2012107498A1 (en) 2011-02-08 2012-08-16 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative disorders
WO2012107499A1 (en) 2011-02-08 2012-08-16 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders
WO2012135113A2 (en) 2011-03-25 2012-10-04 Glaxosmithkline Llc Cyclopropylamines as lsd1 inhibitors
US8853408B2 (en) * 2011-03-25 2014-10-07 Glaxosmithkline Intellectual Property (No. 2) Limited Cyclopropylamines as LSD1 inhibitors
WO2012156531A2 (en) 2011-05-19 2012-11-22 Oryzon Genomics, S.A. Lysine demethylase inhibitors for inflammatory diseases or conditions
WO2012156537A9 (en) 2011-05-19 2013-03-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors such as cyclylcylopropamine derivatives for use in the treatment of thrombosis and cardiovascular diseases
WO2013022047A1 (ja) * 2011-08-09 2013-02-14 武田薬品工業株式会社 シクロプロパンアミン化合物
US20140228405A1 (en) * 2011-08-09 2014-08-14 Takeda Pharmaceutical Company Limited Cyclopropaneamine compound
WO2013057322A1 (en) 2011-10-20 2013-04-25 Oryzon Genomics, S.A. (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors
WO2013057320A1 (en) 2011-10-20 2013-04-25 Oryzon Genomics, S.A. (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors
US20150025054A1 (en) * 2011-10-20 2015-01-22 Oryzon Genomics, S.A. (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors

Non-Patent Citations (251)

* Cited by examiner, † Cited by third party
Title
"Definition of Cancer"-MedicineNetcom Medical references for patients, http://www.medterms.com, 2005.
Ahmed et al, "Ticagrelor: a new reversible oral antiplatelet agent" Int Research Journal of Pharmacy, 2010, 1(1), 62-69.
Arya et al, "Synthesis of 5H-dibenzo[a,d]cycloheptene derivatives with diverse biological activities", Indian J Chemistry B, 1978, 16B,220-225.
Bar-Am et al, "Regualtion of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine". FASEB J, 2005, 19(13),1899-1901.
Barlesi et al, "Global histone modifications predict prognosis of resected non small-cell lung cancer",J Clin Oncol,2007,25, 4358-4364.
Biljak et al,"Platelet count, mean platelet volume and smoking status in stable chronic obstructive pulmonary disease", Platelets, 2011,22(6), 466-70.
Binda et al, "Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2", J Am Chem Soc,2010, 132(19),6827-6833.
Bisi et al, "Multidrug resistance reverting activity and antiumor profile of new phenothiazine derivatives", Bioorg Med Chem, 2008, 16(13), 6474-6482.
Boilard et al., "Platelets amplify inflammation in arthritis via collagen-dependent microparticle production", Science, 2010,327(5965), 580-583.
Bolesov et al, "Cyclopropanes and cyclobutanes LXIX", Zhumal Organicheskoi Khimii (English Translation), 1974, 10(10), 2122-2128.
Bolesov et al, "Cyclopropanes and cyclobutanes LXVIII. N-mono and N,N-disubstituted 1-amino-2-phenylcyclopropanes",Zhurnal Organicheskoi Khimii (English Translation), 1974, 10(6), 1678-84.
Brand and Perrimon, "Targeted gene expression as a means of altering cell fates and generating dominant phenotypes", 1993, Development, 118- 401-415.
Brydon et al, "Platelets, coronary heart disease and stress", Brain, Behavior and Immunity,2006, 20(2), 113-119.
Burakova et al, "N- and O-alkylation of 3-indolylcyclopropytacetic acid derivatives", Russian Chemical Bulletin, 2002, 51(10) 1829-1840.
Burk et al, "Cognitive deficits in spinocerebellar ataxia 2", Brain, 1999,122(4), 769-777.
Cakmak et al, "Platelets: indicator of inflammation in COPD", Int J Med Sci, 2009, 1(5), 227-229.
Calogero et al, "Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma",Cancer Cell International,2004,4, 1.
CAS Registry No. RN1026290-47-7, entered STN Jun. 8, 2008.
CAS Registry No. RN1157140-28-7, entered STN Jun. 14, 2009.
CAS Registry No. RN1218057-33-0, entered STN Apr. 11, 2010.
CAS Registry No. RN1247564-27-7, entered STN Oct. 27, 2010.
CAS Registry No. RN1247717-42-5, entered STN Oct. 27, 2010.
CAS Registry No. RN1247999-77-4, entered STN Oct. 28, 2010.
CAS Registry No. RN1248611-33-7, entered STN Oct. 29, 2010.
CAS Registry No. RN1248913-30-5, entered STN Nov. 1, 2010.
CAS Registry No. RN1248971-98-3, entered STN Nov. 1, 2010.
CAS Registry No. RN1250045-89-6, entered STN Nov. 1, 2010.
CAS Registry No. RN1250199-20-2, entered STN Nov. 1, 2010.
CAS Registry No. RN1250332-49-0, entered STN Nov. 1, 2010.
CAS Registry No. RN1251130-23-0, entered STN Nov. 3, 2010.
CAS Registry No. RN1270634-53-1, entered STN Mar. 27, 2011.
CAS Registry No. RN1273738-91-2, entered STN Apr. 3, 2011.
CAS Registry No. RN1274124-27-4, entered STN Apr. 3, 2011.
CAS Registry No. RN1274681-54-7, entered STN Apr. 4, 2011.
CAS Registry No. RN1280568-04-8, entered STN Apr. 15, 2011.
CAS Registry No. RN1280602-35-8, entered STN Apr. 15, 2011.
CAS Registry No. RN1281516-77-5, entered STN Apr. 17, 2011.
CAS Registry No. RN1281556-75-9, entered STN Apr. 17, 2011.
CAS Registry No. RN1281596-19-7, entered STN Apr. 17, 2011.
CAS Registry No. RN1281615-78-8, entered STN Apr. 17, 2011.
CAS Registry No. RN1281856-83-4, entered STN Apr. 18, 2011.
CAS Registry No. RN1281886-96-1, entered STN Apr. 18, 2011.
CAS Registry No. RN1282014-65-6, entered STN Apr. 18, 2011.
CAS Registry No. RN1282165-83-6, entered STN Apr. 19, 2011.
CAS Registry No. RN1282245-50-4, entered STN Apr. 19, 2011.
CAS Registry No. RN1282292-27-6, entered STN Apr. 19, 2011.
CAS Registry No. RN1282425-35-7, entered STN Apr. 19, 2011.
CAS Registry No. RN1282679-60-0, entered STN Apr. 20, 2011.
CAS Registry No. RN1282773-23-2, entered STN Apr. 20, 2011.
CAS Registry No. RN1282804-36-7, entered STN Apr. 20, 2011.
CAS Registry No. RN1282928-27-1, entered STN Apr. 20, 2011.
CAS Registry No. RN1283337-81-4, entered STN Apr. 21, 2011.
CAS Registry No. RN1283356-05-7, entered STN Apr. 21, 2011.
CAS Registry No. RN1283449-65-9, entered STN Apr. 21, 2011.
CAS Registry No. RN1283533-13-0, entered STN Apr. 21, 2011.
CAS Registry No. RN1283662-53-2, entered STN Apr. 21, 2011.
CAS Registry No. RN1283728-98-2, entered STN Apr. 21, 2011.
CAS Registry No. RN1283887-44-4, entered STN Apr. 22, 2011.
CAS Registry No. RN1284036-80-1, entered STN Apr. 22, 2011.
CAS Registry No. RN1284049-14-4, entered STN Apr. 22, 2011.
CAS Registry No. RN1284310-21-9, entered STN Apr. 22, 2011.
CAS Registry No. RN1285070-57-6, entered STN Apr. 24, 2011.
CAS Registry No. RN1285129-34-1, entered STN Apr. 24, 2011.
CAS Registry No. RN1285144-86-6, entered Apr. 24, 2011.
CAS Registry No. RN1285176-99-9, entered STN Apr. 24, 2011.
CAS Registry No. RN1285178-46-2, entered STN Apr. 24, 2011.
CAS Registry No. RN1285235-05-3, entered STN Apr. 24, 2011.
CAS Registry No. RN1285348-65-3, entered STN Apr. 25, 2011.
CAS Registry No. RN1285612-69-2, entered STN Apr. 25, 2011.
CAS Registry No. RN1290805-79-6, entered STN May 6, 2011.
CAS Registry No. RN1290906-73-8, entered STN May 6, 2011.
CAS Registry No. RN1290912-35-4, entered STN May 6, 2011.
CAS Registry No. RN1290912-36-5, entered STN May 6, 2011.
CAS Registry No. RN1290949-23-3, entered STN May 6, 2011.
CAS Registry No. RN1290949-24-4, entered STN May 6, 2011.
CAS Registry No. RN1290949-25-5, entered STN May 6, 2011.
CAS Registry No. RN1290971-74-2, entered STN May 6, 2011.
CAS Registry No. RN1290972-32-5, entered STN May 6, 2011.
CAS Registry No. RN1291185-62-3, entered STN May 8, 2011.
CAS Registry No. RN1291186-57-6, entered STN May 8, 2011.
CAS Registry No. RN1291186-59-8, entered STN May 8, 2011.
CAS Registry No. RN1291186-64-5, entered STN May 8, 2011.
CAS Registry No. RN1291230-78-8, entered STN May 8, 2011.
CAS Registry No. RN1291273-81-8, entered STN May 8, 2011.
CAS Registry No. RN1291273-82-9, entered STN May 8, 2011.
CAS Registry No. RN1291273-84-1, entered STN May 8, 2011.
CAS Registry No. RN1291273-86-3, entered STN May 8, 2011.
CAS Registry No. RN1291273-87-4, entered STN May 8, 2011.
CAS Registry No. RN1292446-11-7, entered STN May 10, 2011.
CAS Registry No. RN1304214-87-6, entered STN Jun. 2, 2011.
CAS Registry No. RN1304214-96-7, entered STN Jun. 2, 2011.
CAS Registry No. RN1304214-97-8, entered STN Jun. 2, 2011.
CAS Registry No. RN1304215-06-2, entered STN Jun. 2, 2011.
CAS Registry No. RN1304548-37-1, entered STN Jun. 3, 2011.
CAS Registry No. RN1304827-17-5, entered STN Jun. 3, 2011.
CAS Registry No. RN1304845-55-3, entered STN Jun. 3, 2011.
CAS Registry No. RN1304845-63-3, entered STN Jun. 3, 2011.
CAS Registry No. RN1304845-67-7, entered STN Jun. 3, 2011.
CAS Registry No. RN1304845-70-2, entered STN Jun. 3, 2011.
CAS Registry No. RN1304845-72-4, entered STN Jun. 3, 2011.
CAS Registry No. RN1304845-83-7, entered STN Jun. 3, 2011.
CAS Registry No. RN1305397-75-4, entered STN Jun. 5, 2011.
CAS Registry No. RN1305397-86-7, entered STN Jun. 5, 2011.
CAS Registry No. RN1305398-16-6, entered STN Jun. 5, 2011.
CAS Registry No. RN1306275-88-6, entered STN Jun. 5, 2011.
CAS Registry No. RN1306275-95-5 entered STN Jun. 5, 2011.
CAS Registry No. RN1306276-35-6, entered STN Jun. 5, 2011.
CAS Registry No. RN1306322-57-5, entered STN Jun. 6, 2011.
CAS Registry No. RN1306589-39-8, entered STN Jun. 6, 2011.
CAS Registry No. RN1307573-60-9, entered STN Jun. 8, 2011.
CAS Registry No. RN1307574-08-8, entered STN Jun. 8, 2011.
CAS Registry No. RN1308373-68-1, entered STN Jun. 6, 2011.
CAS Registry No. RN220351-33-7, entered STN Mar. 11, 1999.
CAS Registry No. RN844655-03-4, entered STN Mar. 9, 2005.
CAS Registry No. RN846596-02-9, entered STN Mar. 22, 2005.
CAS Registry No. RN848204-13-7, entered STN Apr. 11, 2005.
CAS Registry No. RN848732-87-6, entered STN Apr. 19, 2005.
CAS Registry No. RN848742-47-2, entered STN Apr. 19, 2005.
CAS Registry No. RN848753-47-9, entered STN Apr. 19, 2005.
CAS Registry No. RN903487-42-3, entered STN Aug. 23, 2006.
CAS Registry No. RN918305-55-2, entered STN Jan. 24, 2007.
CAS Registry No. RN959071-98-8, entered STN Dec. 20, 2007.
Casero et al, "Recent advances in the development of polyamine analogues as antimuor agents", J Med Chem, 2009, 52(15),4551-4573.
Chen et al, "Association of insulin resistance and hematologic parameters: study of a middle-aged and elderly chinese population in Taiwan", J Chin Med Assoc,2006, 69(6), 248-253.
Chimenti et al "Synthesis, Stereochemical Identification, and Selective Inhibitory Activity against Human Monoamine Oxidase-B of 2-Methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones". (2008) J. Med. Chem. 51 (16), 4874-4880.
Choi et al "Histone demethylase LSD1 is required to induce skeletal muscle differentiation by regulating myogenic factors" (2010) Biochemical and Biophysical Research Communications 401(3), 327-332.
Choo et al, "Genetic organization and diversity of the hepatitis C virus", Proc Natl Acad Sci,1991, 88,2451-2455.
Co-pending U.S. Appl. No. 13/138,143, filed Jul. 11, 2011.
Co-pending U.S. Appl. No. 13/497,994, filed Mar. 23, 2012.
Co-pending U.S. Appl. No. 13/500,687, filed Apr. 6, 2012.
Co-pending U.S. Appl. No. 13/580,553, filed Aug. 22, 2012.
Co-pending U.S. Appl. No. 13/580,710, filed Aug. 23, 2012.
Co-pending U.S. Appl. No. 13/812,366, filed Jan. 25, 2013.
Co-pending U.S. Appl. No. 13/812,386, filed Jan. 25, 2013.
Co-pending U.S. Appl. No. 13/876,485, filed Mar. 28, 2013.
Co-pending U.S. Appl. No. 13/877,919, filed Apr. 5, 2013.
Co-pending U.S. Appl. No. 13/983,844, filed Aug. 6, 2013.
Co-pending U.S. Appl. No. 14/096,557, filed Dec. 4, 2013.
Co-pending U.S. Appl. No. 14/118,323, filed Nov. 18, 2013.
Co-pending U.S. Appl. No. 14/118,330, filed Nov. 18, 2013.
Co-pending U.S. Appl. No. 14/184,745, filed Feb. 20, 2014.
Co-pending U.S. Appl. No. 14/228,083, filed Mar. 27, 2014.
Co-pending U.S. Appl. No. 14/352,719, filed Apr. 18, 2014.
Co-pending U.S. Appl. No. 14/480,465, filed Sep. 9, 2014.
Culhane et al, "Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors", J Am Chem Soc, 2010,132(9), 3164-3176.
Culhane et al, A mechanism-based inactivator for histone demthylase LSD1, J Am Chem Soc, 2006, 128(14), 4536-4537.
D.M. Gooden et al., "Facile Synthesis of Substituted trans-2-Arylcyclopropylamine Inhibitors of the Human Histone Demethylase LSD1 and Monoamine Oxidases A and B," Bioorganic and Medicinal Chemistry Letters, vol. 18, pp. 3047-3051 (2008).
Danese et al, "Platelets in inflammatory bowel disease: clinical, pathogenic and therapeutic implications", Am J Gastroenterol, 2004,99(5), 938-45.
Delorme et al, HCAPLUS, Document No. 132:49802, "Preparation of 1-(N-substituted aminomethyl)-4-guanidinomethylcyclohexanes useful in pain management", 1999.
Di Stefano et al, Mutation of Drosophila Lsd1 disrupts H3-K4 methylation, resulting in tissue-specific defects during development, Curr Biol,2007, 17(9), 808-12.
East et al, "An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction", Bioorg Med Chem Lett, 2010, 20(16), 4901-5.
Ellis et al, "Expression of Drosophila glass protein and evidence for negative regulation of its activity in non-neuronal cells by another DNA-binding protein",Development,1993, 119, 855-865.
Elsheikh et al "Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors and patient outcome", Canc Res, 2009,69, 3802-3809.
Erazo et al, "Varicella-zoster virus open reading frame 66 protein kinase is required for efficient viral growth in primary human corneal stromal fibroblast cells", J Viral, 2008,82, 7653-7665.
Exhibit "312 amendment" (2016). *
F. Zaragoza Dörwald "Side reactions in Organic Synthesis: a guide to successful synthesis design" Wiley-VCH Verlag GmbH & Co, KGaA, Wilenheim, Chapter 1, 2005.
Faler et al, "The Kulinkovich reaction in the synthesis of constrained N,N-dialkyl neurotransmitter analogues", Organic Letters 2007,9(10),1987-1990.
Ferlay et al, "Estimates of the cancer incidence and mortality in Europe in 2006", Annals of Oncology 2007,18(3), 581-92.
Ferraro et al, "EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer", J Clin Oncol, 2005, 23(9), 1921-26.
Fischer et al, "Recovery of learning and memory is associated with chromatin remodelling", Nature, 2007,447, 178-182.
Forneris et al "LSD1: oxidative chemistry for multifaceted functions in chromatin Regulation." Trends in Biochemical Sciences 2008,33(4), 181-189.
Gawaz et al, "Platelets in inflammation and atherogenesis", J Clin Invest, 2005,115(12), 3378-3384.
Guile et al. "Preparation of triazolo . . . " CA130:168386 (1999). *
H. Benelkebir et al., "Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors," Bioorganic & Medicinal Chemistry, vol. 19, pp. 3709-3716 (2011).
Han et al "Modulation of breast cancer resistance protein (BCRP/ABCG2) by non-basic chalcone analogues" Eur. J. Pharma. 2008, 35(1-2) 30-41.
Han et al, "Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated PC12 cells", Eur J Pharmacol, 2009, 604 (1-3),36-44.
Hayami et al, "Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers", Int J Cancer, 2011, 128(3), 574-86.
Hruschka et al, "Fluorinated phenylcyclopropylarnines, Part 5:Effect of electron-withdrawing or-donating aryl substituents on the inhibition of monoamine oxidases A and B by 2-aryl-2-fluoro-cyclopropyiernines", Bioorg Med Chem,2008, 16(15). 7148-7166.
Huang et al, "Novel oligoamine analogues inhibit lysine-specific demethylase 1 (LSD1) and induce re-expression of epigeneticall silenced genes",Clin Cancer Res,2009, 15(23), 7217-28.
Huang et al, "p53 is regulated by the lysine demethylase LSD1",Nature,2007,449, 105-108.
Huang et al,"Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes", PNAS,2007, 104(19), 8023-8028.
Impoper Markush Fed. Reg. v.76(27) 7162-7175, slide 1, 64-67 (2011-. *
International Search Report of International Application No. PCT/EP2012/070896, dated Mar. 14, 2013.
Jackson et al, "Polyglutamine-expanded human Huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons", Neuron, 1998, 21, 633-642.
Johnson et al, CAPLUS, Document No. 157:578967, "Preparation of cyclopropylamines as LSD1 inhibitors in the treatment of cancer", 2012.
Kahl et al,"Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence", Cancer Res,2006,66 (23), 11341-11347.
Kaiser et al, "2-substituted cyclopropylamines. I. Derivatives and analogs of 2-phenylcyclopropylamine", J Med Pharm Chem (ACS), 1962, 5, 1243-1265.
Kiefmann et al, "Red blood cells induce hypoxic lung inflammation", Blood, 2008,111(10),5205-14.
Kim et al, "Flavin chemical models for monoamine oxidase inactivation by cyclopropylamines, alpha-silylamines, and hydrazines", J Am Chem Soc 1995, 117, 100-105.
Kim et al, "Flavin chemical models for monoamine oxidase inactivation by cyclopropylamines, α-silylamines, and hydrazines", J Am Chem Soc 1995, 117, 100-105.
Kim et. al. "Flavin chemical . . . " CA122:49911 (1995). *
Kinzel et al, "Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a]pyrazine-7-(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies. Part 2", Bioorg Med.Chem Lett 2011, 21(15), 4429-4435.
Kinzel et al. "Identification of . . . " CA155:343885 (2011). *
Kornerup et al, "The role of platelets in the pathophysiology of asthma" Platelets, 2007,18(5), 319-28.
Krieger et al, "Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations", J Virol, 2001,75, 4614-4624.
Lan et al "Mechanisms involved in the regulation of histone lysine demethylases", Current Opinion in Cell Biology, 2008,20, 316-325.
Lang et al, "Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency",Nat Med, 2009,15 (11), 1312-1317.
Lee at al, "Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates", J Comb Chem, 2003, 5(2), 172-187.
Lee et al, "Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications",Chem Biol, 2006,13(6), 563-567.
Li et al, "Association between inflammatory mediators and angiographic morphologic features indicating thrombus formation in patients with acute myocardial infarction", Chin Med J, 2009,122(15), 1738-42.
Lim et al, "Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology", Carcinogenesis,2010, 31(3), 512-20.
Lucerna et al, "Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth",Cancer Research,2006, 66,6708-6713.
Lupu Roxana, "Up-to-date in the hematological malignancies treatment", Maedica, 2006,1(1), 63-65.
MacLay et al, "Increased platelet activation in patients with stable and acute exacerbation of COPD", Thorax, 2011,66(9), 769-74.
Mannaioni et al, "Platelets and inflammation: role of platelet-derived growth factor, adhesion molecules and histamine", Inflamm Res, 1997,46(1), 4-18.
McNicol et al, "Beyond hemostasis: the role of platelets in inflammation, malignancy and infection",Cardiovascular & Haematological Disorders-Drug Targets; 2008,8, 99-117.
Meanwell, "Synopsis of some recent tactical application of bioisosteres in drug design", J Med Chem, 2011, 54(8),2529-91.
Metzger et al, "LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription",Nature,2005, 437(7057),436-9.
Mimasu et al "Crystal structure of histone dernethylase LSD1 and tranylcypromine at 2.95 {hacek over (A)}" Biochemical and Biophysical Research Communications ,2008,366, 15-22.
Moritani et al, "Activation of platelets in bronchial asthma", Chest, 1998,113, 452-458.
Nabil Aboul-Enein et al, "Synthesis of some 4-substituted amino-1-methylpiperidines structurally related to antihistaminics", Pharmaceutica Acta Helvetiae, 1973, 48(3): 151-156.
Neelamegan et al, "Brain-penetrant LSD1 inhibitors can block memory consolidation", ACS Chem Neurosci, 2012, 3(2), 120-128.
New Matter, USPTO connection vol. II(1) p. 1-2 (2005). *
Ogasawara at al, "Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor",Bioorg Med Chem, 2011, doi:10.1016/j.bmc.2010.12.024.
O'Sullivan at al, "The inflammatory role of platelets in cystic fibrosis", Am J Respir Crit Care Med, 2008,173, 483-90.
Pannala at al "Synthesis and structure-activity relationship of 4-(2-aryl-cyclopropylamino)-quinoline-3-carbonitriles as EGFR tyrosine kinase inhibitors". Bioorg & Med Chem Lett , 2007,17(21), 5978-5082.
Patani et al. "bioisosterism . . . " Chem. Rev. 96, 3147-3176 (1996). *
Pitchford at al, "Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation", Blood, 2005,105, 2074-2081.
Pollock at al, Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERalpha-dependent and -independent manners, ACS Chem Biol 2012,7,1221-1231.
Ravina et al, "The relationship between CAG repeat length and clinical progression in Huntington's disease", Movement Disorders,2008,23(9), 1223-7.
Reddy at al, "Role of lysine-specific demethylase 1 in the proinflammatory phenotype of vascular smooth muscle cells of diabetic mice",Circ Res,2008,103, 615-23.
Riley et al, "Absolute configuration of (+)- and (-)-trans-2-phenylcyclopropylamine hydrochloride",J.Med Chem, 1972,15(11), 1187-1188.
Riley et al, "Absolute configuration of (+)- and (−)-trans-2-phenylcyclopropylamine hydrochloride",J.Med Chem, 1972,15(11), 1187-1188.
Rinder at al, "Correlation of thrombosis with increased platelet turnover in thrombocytosis", Blood, 1998,91(4), 1288-1294.
Rubini et al. "Synthesis of isosteric . . . " Tetrhedron v.42(21) 6039-45 (1986). *
S. Minasu et al., "Structurally Designed trans-2-Phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1," Biochemistry, vol. 49, pp. 6494-6503 (2010).
Schmidt at al,"trans-2-phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1", Biochemistry, 2007,46(14),4408-4416.
Schulte at al, "Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy", Cancer Res,2009,69(5),2085-71.
Scoumanne et al "Protein methylation: a new mechanism of p53 tumor suppressor regulation" Histol Histopathol 2008,23, 1143-1149.
Scoumanne et al, "The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and -independent manners", J Biol Chem, 2007,282(21), 15471-5.
Seligson et al, "Global histone modification patterns predict risk of prostate cancer recurrence",Nature, 2005,435, 1262-1266.
Seligson et al,"Global levels of histone modifications predict prognosis in different cancers" ,Am J Path, 2009,174,1619-28.
Sharma et al, "(Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators", J Med Chem, 2010,53(14), 5197-5212.
Shi et al,"Histone demethylation mediated by the nuclear amine oxidase homolog LSD1", Cell, 2004,119,941-953.
Shi, "Histone lysine demethylases: emerging roles in development, physiology and disease", Nature Reviews Genetics 2007, 8:829-833.
Stephens et al, "The determination of the absolute configurations of chiral molecules using vibrational circular dichroism (VCD) spectroscopy",Chirality, 2008,20(5), 643-663.
Stoffel et al, "Leukocyte count and risk of thrombosis in patients undergoing haematopoietic stem cell transplantation or intensive chemotherapy",Thromb Haemost, 2010,103(6), 1228-32.
Stratmann et al, "Pathobiology and cell interactions of platelets in diabetes", Diabetes & Vascular Disease Research,2005, 2(1), 16-23.
Szewczuk et al, "Mechanistic analysis of a suicide inactivator of histone demethylase LSD1", Biochemistry, 2007,46, 6892-6902.
Tamagawa-Mineoka et al, "Elevated platelet activation in patients with atopic dermatitis and psoriasis: increased plasma levels of beta-thromboglobulin and platelet factor 4", Allergology International,2008, 57, 391-396.
Taylor et al,"Roscovitine, a cyclin-dependent kinase inhibitor, prevents replication of varicella-zoster virus", J Virol, 2004,78, 2853-2862.
Thaulow et al, "Blood platelet count and function are related to total and cardiovascular death in apparently healtht men", Circulation, 1991,84, 613-617.
Tyco v Ethicon CAFC blog p. 1 (2014). *
Ueda et al, "Identification of cell-active lysine specific demethylase 1-selective inhibitors",J A Chem Soc, 2009,131(48), 17536-17537.
Vagner et al, "Peptidomimetics, a synthetic tool of drug discovery" Current Opinion on Chemical Biology, 2008, 12:292-296.
Wagner at al, "Platelets in inflammation and thrombosis", Arteriosclerosis, Thrombosis and Vascular Biology, 2003,23, 2131-2137.
Wang at al, "The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation", Nature Genetics, 2009,41(1), 125-129.
Wang at el "LSD1 Is a Subunit of the NuRD Complex and Targets the Metastasis Programs in Breast Cancer" Cell 2009, 138, 660-672.
Wang et al, Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties, Cancer Research, 2011, 71(23):7238-49.
Weinreb et al, "Novel neuroprotective mechanism of action of rasagiline is associated with its propargyl moiety: interaction of Bcl-2 family members with PKC pathway", Ann NY Acad Sci, 2005,1053, 348-55.
Wermuth, "Molecular variations based on isosteric replacements", The Practice of Medicinal Chemistry (2nd edition), Academic Press, London, 2003, pp. 189-214.
Westland at al , "N-substituted derivatives of 2-aminoethanethiol and 2-hydraxinoethanethiol", JMedChem 1968, 11(4),824-829.
Whitlow at al,"Recruitment of tie transcriptional coact HCF-1 to viral immediate-early promoters during initiation of reactivation from latency of herpes simplex virus type 1", J Virol, 2009,83(18):9591-5.
Willoughby et al; "Platelets and cardiovascular disease",Eur J Cardiovasc Nursing,2002,1, 273-288.
Written Opinion of the International Searching Authority for PCT/EP2012/070898, dated Mar. 14, 2013.
XP002568777 Database chemcats, database accession No. 2088922753, order No. kbsb-0063197, Aurora screening library, Aug. 20, 2009.
Yang at al "Structural basis of histone demethylation by LSD1 revealed by suicide inactivation" Nature Strutural & Molecular Biology 2007, 14(6), 535-539.
Yang et al "Structural Basis for the Inhibition of the LSD1 Histone Demethylase by the Antidepressant trans-2-Phenylcyclopropylamine" Biochemistry 2007,46 (27), 8058-8065.
Yoshida et al, "Fluorinated phenylcyclopropylammes, Part 3: inhibition of monoamine oxidase A and B",Bioorg Med Chem,2004,12(10),2645-2852.
Youdim et al, "Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases", Mechanisms of Ageing and Development, 2005, 126: 317-326.
Zirkle et al, "2-substituted cyclopropylamines. II. Effect of structure upon monoamine oxidase-inhibitory activity as measured in vivo by potentiation of tryptamine convulsions", J Med Pharma Chem (ACS), 1962, 5, 1265-84.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9944601B2 (en) 2011-10-20 2018-04-17 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10214477B2 (en) 2011-10-20 2019-02-26 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10329256B2 (en) 2011-10-20 2019-06-25 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10221125B2 (en) 2015-05-06 2019-03-05 Oryzon Genomics, S.A. Solid forms
US10265279B2 (en) 2016-03-15 2019-04-23 Oryzon Genomics, S.A. Combinations of LSD1 inhibitors for use in the treatment of solid tumors
US11013698B2 (en) 2016-03-15 2021-05-25 Oryzon Genomics S.A. Combinations of LSD1 inhibitors for the treatment of hematological malignancies
US10780081B2 (en) 2016-06-10 2020-09-22 Oryzon Genomics, S.A. Method of treating multiple sclerosis employing a LSD1-inhibitor

Also Published As

Publication number Publication date
EP2768805B1 (en) 2020-03-25
CN107266345A (zh) 2017-10-20
CA2852355C (en) 2019-12-31
KR20140081884A (ko) 2014-07-01
CA2852355A1 (en) 2013-04-25
EP3736265A1 (en) 2020-11-11
US9944601B2 (en) 2018-04-17
US20150025054A1 (en) 2015-01-22
BR112014009306A2 (pt) 2017-04-11
AU2017254889B2 (en) 2019-05-16
MX2014004429A (es) 2015-02-10
US20170008844A1 (en) 2017-01-12
US10329256B2 (en) 2019-06-25
JP2017226671A (ja) 2017-12-28
JP6382403B2 (ja) 2018-08-29
JP6215212B2 (ja) 2017-10-18
CN104203914B (zh) 2017-07-11
MX356344B (es) 2018-05-23
KR102139537B1 (ko) 2020-07-31
CN104203914A (zh) 2014-12-10
AU2012324803B9 (en) 2017-08-24
AU2012324803A1 (en) 2014-06-05
CN107266345B (zh) 2021-08-17
RU2014120210A (ru) 2015-11-27
RU2681211C2 (ru) 2019-03-05
WO2013057320A1 (en) 2013-04-25
EP2768805A1 (en) 2014-08-27
IL232102A0 (en) 2014-05-28
IL232102A (en) 2017-12-31
JP2014532619A (ja) 2014-12-08
HK1205110A1 (en) 2015-12-11
AU2012324803A8 (en) 2014-08-14
AU2017254889A1 (en) 2017-11-23
AU2012324803B2 (en) 2017-08-03
US20180354902A1 (en) 2018-12-13
BR112014009306B1 (pt) 2021-07-20

Similar Documents

Publication Publication Date Title
US10329256B2 (en) (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10214477B2 (en) (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
DK2776394T3 (en) (HETERO) ARYLCYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
HK1205110B (en) (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors
HK1200457B (en) (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors
NZ622656B2 (en) (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: ORYZON GENOMICS S.A., SPAIN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MUNOZ, ALBERTO ORTEGA;FYFE, MATTHEW COLIN THOR;PEDEMONTE, MARC MARTINELL;AND OTHERS;SIGNING DATES FROM 20160708 TO 20160711;REEL/FRAME:039430/0763

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 8